Author: "Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM)" - Searchworks@Jio Institute Digital Library Search Results

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642 results on '"Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM)"'

1. Understanding functional neurological disorders: From biological markers to pathophysiological models

Author: Conejero, Ismael, Thouvenot, Eric, Hingray, Coraline, Hubsch, Cécile, El-Hage, Wissam, Carle-Toulemonde, Guilhem, Rotge, Jean-Yves, Drapier, Sophie, Drapier, Dominique, Mouchabac, Stéphane, Centre Hospitalier Universitaire de Nîmes (CHU Nîmes), Institut de Génomique Fonctionnelle - Montpellier GenomiX (IGF MGX), Institut de Génomique Fonctionnelle (IGF), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM)-BioCampus (BCM), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre Psychothérapique de Nancy [Laxou] (CPN), Fondation Ophtalmologique Adolphe de Rothschild [Paris], Clinique Psychiatrique Universitaire [Tours], Centre Hospitalier Régional Universitaire de Tours (CHRU Tours), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Centre d'Investigation Clinique [Rennes] (CIC), Université de Rennes (UR)-Hôpital Pontchaillou-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Pontchaillou [Rennes], Université de Rennes (UR), Centre Hospitalier Guillaume Régnier [Rennes], Institut du Cerveau = Paris Brain Institute (ICM), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), and None
Subjects: [SDV]Life Sciences [q-bio], Neurosciences, Neuroimaging, Trouble neurologique fonctionnel, Functional neurological disorders, Stress, Neuroimagerie, Neuroscience
Abstract: National audience; OBJECTIVES: Functional neurological disorders have witnessed intense research activity in the fields of structural and functional neuroimaging for more than twenty years. Thus, we propose a synthesis of recent research findings and etiological hypotheses that have been proposed so far. This work should help clinicians to better understand the nature of the mechanisms involved, but also help patients to increase their knowledge about the biological features underlying their functional symptoms. METHODS: We carried out a narrative review of international publications dealing with neuroimaging and biology of functional neurological disorders, from 1997 to 2023. RESULTS: Several brain networks underlie functional neurological symptoms. These networks play a role in the management of cognitive resources, in attentional control, emotion regulation, in agency and in the processing of interoceptive signals. The mechanisms of the stress response are also associated with the symptoms. The biopsychosocial model helps to better understand predisposing, precipitating, and perpetuating factors involved. The functional neurological phenotype results from the interaction between: i) a specific pre-existing vulnerability resulting from biological background and epigenetic modifications, and ii) exposure to stress factors, according to the stress-diathesis model. This interaction causes emotional disturbances including hypervigilance, lack of integration of sensations and affects, and emotional dysregulation. These characteristics in turn impact the cognitive, motor and affective control processes related with the functional neurological symptoms. CONCLUSIONS: A better knowledge of the biopsychosocial determinants of brain network dysfunctions is necessary. Understanding them would help developing targeted treatments, but is also critical for patients care.
Published: 2023

2. Glutaredoxin regulation of primary root growth confers early drought stress tolerance in pearl millet

Author: Carla de la Fuente, Alexandre Grondin, Bassirou Sine, Marilyne Debieu, Christophe Belin, Amir Hajjarpoor, Jonathan A. Atkinson, Sixtine Passot, Marine Salson, Julie Orjuela, Christine Tranchant-Dubreuil, Jean-Rémy Brossier, Maxime Steffen, Charlotte Morgado, Hang Ngan Dinh, Bipin K. Pandey, Julie Darmau, Antony Champion, Anne- Sophie Petitot, Celia Barrachina, Marine Pratlong, Thibault Mounier, Pascal Gantet, Prakash Gangashetty, Yann Guédon, Vincent Vadez, Jean-Philippe Reichheld, Malcolm J. Bennett, Ndjido Kane, Soazig Guyomarc’h, Darren M. Wells, Yves Vigouroux, Laurent Laplaze, Diversité, adaptation, développement des plantes (UMR DIADE), Centre de Coopération Internationale en Recherche Agronomique pour le Développement (Cirad)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD [France-Sud])-Université de Montpellier (UM), LMI Adaptation des Plantes et microorganismes associés aux Stress Environnementaux [Dakar] (LAPSE), Institut de Recherche pour le Développement (IRD), Centre d'Etude Regional Pour l'Amelioration de l'Adaptation A la Secheresse (CERAAS), Institut Sénégalais de Recherches Agricoles [Dakar] (ISRA), Laboratoire Génome et développement des plantes (LGDP), Université de Perpignan Via Domitia (UPVD)-Centre National de la Recherche Scientifique (CNRS), University of Nottingham, UK (UON), Institut de Génomique Fonctionnelle - Montpellier GenomiX (IGF MGX), Institut de Génomique Fonctionnelle (IGF), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM)-BioCampus (BCM), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), International Crops Research Institute for the Semi-Arid Tropics [Inde] (ICRISAT), Consultative Group on International Agricultural Research [CGIAR] (CGIAR), Amélioration génétique et adaptation des plantes méditerranéennes et tropicales (UMR AGAP), Centre de Coopération Internationale en Recherche Agronomique pour le Développement (Cirad)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Institut Agro Montpellier, Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro)-Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro)-Université de Montpellier (UM), Agropolis Fondation (NewPearl grant n° AF 1301-015 in the frame of the CERES initiative, ValoRoot grant n°2202-002, and Flagship Project CalClim grant no. 1802-002)Fondazione Cariplo (n° FC 2013-0891)- CGIAR Research Programme on Grain Legumes and Dryland Cereals (GLDC), ANR-17-CE20-0022,RootAdapt,Traits racinaires pour l'adaptation du mil au climat futur en Afrique de l'Ouest(2017), ANR-10-LABX-0001,AGRO,Agricultural Sciences for sustainable Development(2010), ANR-16-IDEX-0006,MUSE,MUSE(2016), and European Project
Subjects: [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], [SDV.BV.BOT]Life Sciences [q-bio]/Vegetal Biology/Botanics
Abstract: Seedling root traits impact plant establishment under challenging environments. Pearl millet is one of the most heat and drought tolerant cereal crops that provides a vital food source across the sub-Saharan Sahel region. Pearl millet’s early root system features a single fast-growing primary root which we hypothesize is an adaptation to the Sahelian climate. Using crop modelling, we demonstrate that early drought stress is an important constraint in agrosystems in the Sahel where pearl millet was domesticated. Furthermore, we show that increased pearl millet primary root growth is correlated with increased early water stress tolerance in field conditions. Genetics including GWAS and QTL approaches identify genomic regions controlling this key root trait. Combining gene expression data, re-sequencing and re- annotation of one of these genomic regions identified a glutaredoxin-encoding genePgGRXC9as the candidate stress resilience root growth regulator. Functional characterization of its closest Arabidopsis homologAtROXY19revealed a novel role for this glutaredoxin (GRX) gene clade in regulating cell elongation. In summary, our study suggests a conserved function for GRX genes in conferring root cell elongation and enhancing resilience of pearl millet to its Sahelian environment.
Published: 2023

3. Whole blood transcriptome profiles of trypanotolerant and trypanosusceptible cattle highlight a differential modulation of metabolism and immune response during infection by Trypanosoma congolense

Author: Moana Peylhard, David Berthier, Guiguigbaza-Kossigan Dayo, Isabelle Chantal, Souleymane Sylla, Sabine Nidelet, Emeric Dubois, Guillaume Martin, Guilhem Sempéré, Laurence Flori, Sophie Thévenon, Interactions hôtes-vecteurs-parasites-environnement dans les maladies tropicales négligées dues aux trypanosomatides (UMR INTERTRYP), Centre de Coopération Internationale en Recherche Agronomique pour le Développement (Cirad)-Institut de Recherche pour le Développement (IRD)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Université de Bordeaux (UB), Département Systèmes Biologiques (Cirad-BIOS), Centre de Coopération Internationale en Recherche Agronomique pour le Développement (Cirad), Centre international de recherche-développement sur l'élevage en zone sub-humide (CIRDES), Institut de Génomique Fonctionnelle - Montpellier GenomiX (IGF MGX), Institut de Génomique Fonctionnelle (IGF), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM)-BioCampus (BCM), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut des Sciences de l'Evolution de Montpellier (UMR ISEM), Centre de Coopération Internationale en Recherche Agronomique pour le Développement (Cirad)-École Pratique des Hautes Études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université de Montpellier (UM)-Institut de recherche pour le développement [IRD] : UR226-Centre National de la Recherche Scientifique (CNRS), Amélioration génétique et adaptation des plantes méditerranéennes et tropicales (UMR AGAP), Centre de Coopération Internationale en Recherche Agronomique pour le Développement (Cirad)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Institut Agro Montpellier, Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro)-Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro)-Université de Montpellier (UM), Systèmes d'élevage méditerranéens et tropicaux (UMR SELMET), Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro)-Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro), ANR-11-JSV6-0001,AATTOL,Caractérisation des bases moléculaires de la tolérance à la Trypanosomose Animale Africaine: analyse conjointe des transcriptomes de l'hôte bovin et du parasite(2011), ANR-11-LABX-0024,ParaFrap,Alliance française contre les maladies parasitaires(2011), and ANR-10-INBS-0009,France-Génomique,Organisation et montée en puissance d'une Infrastructure Nationale de Génomique(2010)
Subjects: Trypanosoma congolense, [SDV]Life Sciences [q-bio]
Abstract: Animal African trypanosomosis, caused by blood protozoan parasites transmitted mainly by tsetse flies, represents a major constraint for millions of cattle in sub-Saharan Africa. Exposed cattle include trypanosusceptible indicine breeds, severely affected by the disease, and West African taurine breeds called trypanotolerant owing to their ability to control parasite development, survive and grow in enzootic areas. Until now the genetic basis of trypanotolerance remains unclear. Here, to improve knowledge of the biological processes involved in trypanotolerance versus trypanosusceptibility, we identified bovine genes differentially expressed in five West African cattle breeds during an experimental infection byTrypanosoma congolenseand their biological functions. To this end, whole blood genome-wide transcriptome of three trypanotolerant taurine breeds (N’Dama, Lagune and Baoulé), one susceptible zebu (Zebu Fulani) and one African taurine x zebu admixed breed (Borgou) were profiled by RNA sequencing at four time points, one before and three during infection. As expected, infection had a major impact on cattle blood transcriptome regardless of the breed. The functional analysis of differentially expressed genes over time in each breed confirmed an early activation of the innate immune response, followed by an activation of the humoral response and an inhibition of T cell functions at the chronic stage of infection. More importantly, we highlighted overlooked features, such as a strong disturbance in host metabolism and cellular energy production that differentiates trypanotolerant and trypanosusceptible breeds. N’Dama breed showed the earliest regulation of immune response, associated with a strong activation of cellular energy production, also observed in Lagune, and to a lesser extent in Baoulé. Susceptible Zebu Fulani breed differed from other breeds by the strongest modification in lipid metabolism regulation. Overall, this study provides a better understanding of the biological mechanisms at work during infection, especially concerning the interplay between immunity and metabolism that seems differentially regulated depending on the cattle breeds.
Published: 2023

4. First chromosome scale genomes of ithomiine butterflies (Nymphalidae: Ithomiini): comparative models for mimicry genetic studies

Author: Jérémy Gauthier, Joana Meier, Fabrice Legeai, Melanie McClure, Annabel Whibley, Anthony Bretaudeau, Hélène Boulain, Hugues Parrinello, Sam T. Mugford, Richard Durbin, Chenxi Zhou, Shane McCarthy, Christopher W. Wheat, Florence Piron‐Prunier, Christelle Monsempes, Marie‐Christine François, Paul Jay, Camille Noûs, Emma Persyn, Emmanuelle Jacquin‐Joly, Camille Meslin, Nicolas Montagné, Claire Lemaitre, Marianne Elias, Natural History Museum [Geneva], Department of Zoology [Cambridge], University of Cambridge [UK] (CAM), Institut de Génétique, Environnement et Protection des Plantes (IGEPP), Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Institut Agro Rennes Angers, Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro)-Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro), Institut de Recherche en Informatique et Systèmes Aléatoires (IRISA), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Institut National des Sciences Appliquées - Rennes (INSA Rennes), Institut National des Sciences Appliquées (INSA)-Université de Rennes (UNIV-RENNES)-Institut National des Sciences Appliquées (INSA)-Université de Bretagne Sud (UBS)-École normale supérieure - Rennes (ENS Rennes)-Institut National de Recherche en Informatique et en Automatique (Inria)-CentraleSupélec-Centre National de la Recherche Scientifique (CNRS)-IMT Atlantique (IMT Atlantique), Institut Mines-Télécom [Paris] (IMT)-Institut Mines-Télécom [Paris] (IMT), Scalable, Optimized and Parallel Algorithms for Genomics (GenScale), Inria Rennes – Bretagne Atlantique, Institut National de Recherche en Informatique et en Automatique (Inria)-Institut National de Recherche en Informatique et en Automatique (Inria)-GESTION DES DONNÉES ET DE LA CONNAISSANCE (IRISA-D7), Institut Mines-Télécom [Paris] (IMT)-Institut Mines-Télécom [Paris] (IMT)-Université de Rennes 1 (UR1), Institut Mines-Télécom [Paris] (IMT)-Institut Mines-Télécom [Paris] (IMT)-Institut de Recherche en Informatique et Systèmes Aléatoires (IRISA), Institut National des Sciences Appliquées (INSA)-Université de Rennes (UNIV-RENNES)-Institut National des Sciences Appliquées (INSA)-Université de Bretagne Sud (UBS)-École normale supérieure - Rennes (ENS Rennes)-CentraleSupélec-Centre National de la Recherche Scientifique (CNRS)-IMT Atlantique (IMT Atlantique), Institut de Systématique, Evolution, Biodiversité (ISYEB ), Muséum national d'Histoire naturelle (MNHN)-École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Université des Antilles (UA), Laboratoire Ecologie, Evolution, Interactions des Systèmes amazoniens (LEEISA), Institut Français de Recherche pour l'Exploitation de la Mer (IFREMER)-Université de Guyane (UG)-Centre National de la Recherche Scientifique (CNRS), School of Biological Sciences [Auckland], University of Auckland [Auckland], Department of Ecology and Evolution [Lausanne], Université de Lausanne = University of Lausanne (UNIL), Institut de Génomique Fonctionnelle - Montpellier GenomiX (IGF MGX), Institut de Génomique Fonctionnelle (IGF), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM)-BioCampus (BCM), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), John Innes Centre [Norwich], Biotechnology and Biological Sciences Research Council (BBSRC), Department of Crop Genetics, Biotechnology and Biological Sciences Research Council (BBSRC)-Biotechnology and Biological Sciences Research Council (BBSRC), Department of Genetics [Cambridge], The Wellcome Trust Sanger Institute [Cambridge], Stockholm University, Institut d'écologie et des sciences de l'environnement de Paris (iEES Paris ), Institut de Recherche pour le Développement (IRD)-Sorbonne Université (SU)-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12)-Centre National de la Recherche Scientifique (CNRS)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Ecologie Systématique et Evolution (ESE), AgroParisTech-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS), Laboratoire Cogitamus, Peuplements végétaux et bioagresseurs en milieu tropical (UMR PVBMT), Centre de Coopération Internationale en Recherche Agronomique pour le Développement (Cirad)-Institut de Recherche pour le Développement (IRD)-Université de La Réunion (UR)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), ME acknowledges financial support from ANR (projects SPECREP, ANR-14-CE02-0011, and CLEARWING, ANR-16-CE02-0012) and HFSP (RGP0014/2016). MGX acknowledges financial support from France Génomique National infrastructure, funded as part of 'Investissement d’Avenir' program managed by Agence Nationale pour la Recherche (contract ANR-10-INBS-0009). RD, SM and CZ acknowledge financial support from Wellcome grant WT207492, and SM and work at the Wellcome Sanger Institute were also supported by Wellcome grant WT206194. We thank members of the Wellcome Sanger Institute Scientific Operations and Tree of Life core groups for their contributions to data production and assembly for the Melinaea genomes. We thank Mario Tuanama and Ronald Mori-Pezo for help with rearing and collecting butterflies. MM acknowledges a postdoctoral fellowship by the Fonds Québécois de la Recherche sur la Nature et les Technologies (FQRNT). STM acknowledges support from the BBSRC Institute Strategy Programme (BB/P012574/1). We thank the Peruvian authorities for research permits (236-2012-AG-DGFFS-DGEFFS, 201-2013-MINAGRI-DGFFS/DGEFFS, 002-2015-SERFOR-DGGSPFFS and 373-2017-SERFOR-DGGSPFFS), the Gobierno Regional San Martín PEHCBM (permit: 124-2016-GRSM/PEHCBM-DMA/EII-ANP/JARR) and the Museo de Historia Natural and Prof. Gerardo Lamas for their support. We thank the GenOuest BioInformatics Platform (http://www.genouest.org), which allowed the use of a computing cluster for bioinformatic analyses., ANR-14-CE02-0011,SPECREP,Répétabilité du processus de spéciation chez les papillons: replications naturelles dans une zone de suture(2014), ANR-16-CE02-0012,CLEARWING,La transparence : origine physique, fonctions adaptatives et évolution chez les papillons transparents(2016), ANR-10-INBS-0009,France-Génomique,Organisation et montée en puissance d'une Infrastructure Nationale de Génomique(2010), Gauthier, Jérémy [0000-0001-6666-1002], Meier, Joana [0000-0001-7726-2875], Whibley, Annabel [0000-0003-1878-7705], Parrinello, Hugues [0000-0002-1151-001X], Wheat, Christopher W [0000-0003-1863-2340], Apollo - University of Cambridge Repository, Université de Rennes (UR)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Institut Agro Rennes Angers, Université de Rennes (UR)-Institut National des Sciences Appliquées - Rennes (INSA Rennes), Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Université de Bretagne Sud (UBS)-École normale supérieure - Rennes (ENS Rennes)-Institut National de Recherche en Informatique et en Automatique (Inria)-CentraleSupélec-Centre National de la Recherche Scientifique (CNRS)-IMT Atlantique (IMT Atlantique), Institut Mines-Télécom [Paris] (IMT)-Institut Mines-Télécom [Paris] (IMT)-Université de Rennes (UR)-Institut National des Sciences Appliquées - Rennes (INSA Rennes), Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Université de Bretagne Sud (UBS)-École normale supérieure - Rennes (ENS Rennes)-CentraleSupélec-Centre National de la Recherche Scientifique (CNRS)-IMT Atlantique (IMT Atlantique), Muséum national d'Histoire naturelle (MNHN)-École Pratique des Hautes Études (EPHE), International Aphid Genomics Consortium (IAGC), Department of Crop Genetics [Norwich], and Department of Zoology [Stockholm]
Subjects: ithomiine butterflies, Genomics, chromosome-level genome, Adaptation, Physiological, Chromosomes, Phenotype, Hi-C, Genetics, Animals, [INFO.INFO-BI]Computer Science [cs]/Bioinformatics [q-bio.QM], Butterflies, Ecology, Evolution, Behavior and Systematics, mimicry, Biotechnology, Butterflies/genetics, Chromosomes/genetics, olfaction
Abstract: Funder: Human Frontier Science Program; Id: http://dx.doi.org/10.13039/501100000854, The ithomiine butterflies (Nymphalidae: Danainae) represent the largest known radiation of Müllerian mimetic butterflies. They dominate by number the mimetic butterfly communities, which include species such as the iconic neotropical Heliconius genus. Recent studies on the ecology and genetics of speciation in Ithomiini have suggested that sexual pheromones, colour pattern and perhaps hostplant could drive reproductive isolation. However, no reference genome was available for Ithomiini, which has hindered further exploration on the genetic architecture of these candidate traits, and more generally on the genomic patterns of divergence. Here, we generated high-quality, chromosome-scale genome assemblies for two Melinaea species, M. marsaeus and M. menophilus, and a draft genome of the species Ithomia salapia. We obtained genomes with a size ranging from 396 to 503 Mb across the three species and scaffold N50 of 40.5 and 23.2 Mb for the two chromosome-scale assemblies. Using collinearity analyses we identified massive rearrangements between the two closely related Melinaea species. An annotation of transposable elements and gene content was performed, as well as a specialist annotation to target chemosensory genes, which is crucial for host plant detection and mate recognition in mimetic species. A comparative genomic approach revealed independent gene expansions in ithomiines and particularly in gustatory receptor genes. These first three genomes of ithomiine mimetic butterflies constitute a valuable addition and a welcome comparison to existing biological models such as Heliconius, and will enable further understanding of the mechanisms of adaptation in butterflies.
Published: 2023

5. In vivo investigation of Lcr35® anti-candidiasis properties in Caenorhabditis elegans reveals the involvement of highly conserved immune pathways

Author: Cyril Poupet, Étienne Rifa, Sébastien Theil, Muriel Bonnet, Philippe Veisseire, Guillaume Cardin, Élise Guéret, Stéphanie Rialle, Christophe Chassard, Adrien Nivoliez, Stéphanie Bornes, Unité Mixte de Recherche sur le Fromage (UMRF), VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Université Clermont Auvergne (UCA), Institut de Génomique Fonctionnelle - Montpellier GenomiX (IGF MGX), Institut de Génomique Fonctionnelle (IGF), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM)-BioCampus (BCM), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), and biose Industrie
Subjects: mechanisms of action, Microbiology (medical), host response, [SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, LBM, Caenorhabditis elegans, candidiasis, [SDV.MP.BAC]Life Sciences [q-bio]/Microbiology and Parasitology/Bacteriology, Microbiology, probiotic
Abstract: Lactic acid bacteria, including the microorganisms formerly designated as Lactobacillus, are the major representatives of Live Biotherapeutic Microorganisms (LBM) when used for therapeutic purposes. However, in most cases, the mechanisms of action remain unknown. The antifungal potential of LBM has already been demonstrated using preclinical models (cell cultures, laboratory animals). Understanding their mechanisms of action is strategic for the development of new therapeutics for humans. Here, Caenorhabditis elegans was used as an in vivo model to analyze pro-longevity, anti-aging and anti-candidiasis effects of the LBM Lacticaseibacillus rhamnosus (formerly Lactobacillus rhamnosus) Lcr35®. A high-throughput transcriptomic analysis revealed a specific response of C. elegans depending on whether it is in the presence of the LBM L. rhamnosus Lcr35® (structural response), the yeast Candida albicans (metabolic response) or both (structural and metabolic responses) in a preventive and a curative conditions. Studies on C. elegans mutants demonstrated that the p38 MAPK (sek-1, skn-1) and the insulin-like (daf-2, daf-16) signaling pathways were involved in the extended lifespan provided by L. rhamnosus Lcr35® strain whereas the JNK pathway was not involved (jnk-1). In addition, the anti C. albicans effect of the bacterium requires the daf-16 and sek-1 genes while it is independent of daf-2 and skn-1. Moreover, the anti-aging effect of Lcr35®, linked to the extension of longevity, is not due to protection against oxidative stress (H2O2). Taken together, these results formally show the involvement of the p38 MAP kinase and insulin-like signaling pathways for the longevity extension and anti-Candida albicans properties of Lcr35® with, however, differences in the genes involved. Overall, these findings provide new insight for understanding the mechanisms of action of a probiotic strain with antimicrobial potential.
Published: 2022
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6. Genetic control of rhizosheath formation in pearl millet

Author: de la Fuente Cantó, C., Diouf, M, Ndour, P, Debieu, M., Grondin, A., Passot, S., Champion, A., Barrachina, C., Pratlong, M., Gantet, P., Assigbetsé, K., Kane, N., Cubry, P., Diedhiou, A, Heulin, T., Achouak, W., Vigouroux, Y., Cournac, Laurent, Laplaze, Laurent, Diversité, adaptation, développement des plantes (UMR DIADE), Centre de Coopération Internationale en Recherche Agronomique pour le Développement (Cirad)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD [France-Sud])-Université de Montpellier (UM), Ecologie fonctionnelle et biogéochimie des sols et des agro-écosystèmes (UMR Eco&Sols), Centre de Coopération Internationale en Recherche Agronomique pour le Développement (Cirad)-Institut de Recherche pour le Développement (IRD)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Institut Agro Montpellier, Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro)-Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro), LMI IESOL Intensification Ecologique des Sols Cultivés en Afrique de l’Ouest [Dakar] (IESOL), Institut de recherche pour le développement (IRD [Sénégal]), Université Cheikh Anta Diop [Dakar, Sénégal] (UCAD), LMI Adaptation des Plantes et microorganismes associés aux Stress Environnementaux [Dakar] (LAPSE), Institut de Recherche pour le Développement (IRD), Centre d'Etude Regional Pour l'Amelioration de l'Adaptation A la Secheresse (CERAAS), Institut de Génomique Fonctionnelle - Montpellier GenomiX (IGF MGX), Institut de Génomique Fonctionnelle (IGF), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM)-BioCampus (BCM), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Laboratoire d'Ecologie Microbienne de la Rhizosphère et d'Environnements Extrêmes (LEMIRE), Institut de Biosciences et Biotechnologies d'Aix-Marseille (ex-IBEB) (BIAM), Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS)-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS)-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Ecosystèmes continentaux et risques environnementaux (ECCOREV), Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS), French National Research Institute for Sustainable Development (IRD), CGIAR Research Programme on Grain Legumes and Dryland Cereals (GLDC), NewPearl grant in the frame of the CERES initiative by the Agropolis Fondation, Fondazione Cariplo (No FC 2013-0891), ANR-17-CE20-0022,RootAdapt,Traits racinaires pour l'adaptation du mil au climat futur en Afrique de l'Ouest(2017), ANR-16-IDEX-0006,MUSE,MUSE(2016), ANR-10-LABX-0001,AGRO,Agricultural Sciences for sustainable Development(2010), Fournier, Dominique, Traits racinaires pour l'adaptation du mil au climat futur en Afrique de l'Ouest - - RootAdapt2017 - ANR-17-CE20-0022 - AAPG2017 - VALID, MUSE - - MUSE2016 - ANR-16-IDEX-0006 - IDEX - VALID, and Agricultural Sciences for sustainable Development - - AGRO2010 - ANR-10-LABX-0001 - LABX - VALID
Subjects: [SDV.GEN.GPL]Life Sciences [q-bio]/Genetics/Plants genetics, [SDV.GEN.GPL] Life Sciences [q-bio]/Genetics/Plants genetics, food and beverages
Abstract: International audience; The rhizosheath, the layer of soil that adheres strongly to roots, influences water and nutrients acquisition. Pearl millet is a cereal crop that plays a major role for food security in arid regions of sub-Saharan Africa and India. We previously showed that root-adhering soil mass is a heritable trait in pearl millet and that it correlates with changes in rhizosphere microbiota structure and functions. Here, we studied the correlation between root-adhering soil mass and root hair development, root architecture, and symbiosis with arbuscular mycorrhizal fungi and we analysed the genetic control of this trait using genome wide association (GWAS) combined with bulk segregant analysis and gene expression studies. Root-adhering soil mass was weakly correlated only to root hairs traits in pearl millet. Twelve QTLs for rhizosheath formation were identified by GWAS. Bulk segregant analysis on a biparental population validated five of these QTLs. Combining genetics with a comparison of global gene expression in the root tip of contrasted inbred lines revealed candidate genes that might control rhizosheath formation in pearl millet. Our study indicates that rhizosheath formation is under complex genetic control in pearl millet and suggests that it is mainly regulated by root exudation.
Published: 2022

7. Single cell RNA sequencing reveals hemocyte heterogeneity in Biomphalaria glabrata: Plasticity over diversity

Author: Pichon, Rémi, Pinaud, Silvain, Vignal, Emmanuel, Chaparro, Cristian, Pratlong, Marine, Portet, Anaïs, Duval, David, Galinier, Richard, Gourbal, Benjamin, Apollo - University of Cambridge Repository, Interactions Hôtes-Pathogènes-Environnements (IHPE), Université de Perpignan Via Domitia (UPVD)-Institut Français de Recherche pour l'Exploitation de la Mer (IFREMER)-Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM), Cancer Research UK Cambridge Institute [Cambridge, Royaume-Uni] (CRUK), University of Cambridge [UK] (CAM), Institut de Génomique Fonctionnelle (IGF), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM), Institut de Génomique Fonctionnelle - Montpellier GenomiX (IGF MGX), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM)-BioCampus (BCM), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Wellcome Trust-Medical Research Council Cambridge Stem Cell Institute, and Modat, Anne
Subjects: glabrata, Biomphalaria, Sequence Analysis, RNA, Snails, Immunology, innate immune system, Schistosoma mansoni, mansoni, B. glabrata, [SDV.IMM.II]Life Sciences [q-bio]/Immunology/Innate immunity, Schistosomiasis mansoni, [SDV.BA.ZI]Life Sciences [q-bio]/Animal biology/Invertebrate Zoology, hemocytes, [SDV.BA.ZI] Life Sciences [q-bio]/Animal biology/Invertebrate Zoology, Animals, Humans, Immunology and Allergy, S. mansoni, [SDV.IMM.II] Life Sciences [q-bio]/Immunology/Innate immunity, single cell RNA seq
Abstract: Peer reviewed: True, The freshwater snail Biomphalaria glabrata is an intermediate host of Schistosoma mansoni, the agent of human intestinal schistosomiasis. However, much is to be discovered about its innate immune system that appears as a complex black box, in which the immune cells (called hemocytes) play a major role in both cellular and humoral response towards pathogens. Until now, hemocyte classification has been based exclusively on cell morphology and ultrastructural description and depending on the authors considered from 2 to 5 hemocyte populations have been described. In this study, we proposed to evaluate the hemocyte heterogeneity at the transcriptomic level. To accomplish this objective, we used single cell RNA sequencing (scRNAseq) technology coupled to a droplet-based system to separate hemocytes and analyze their transcriptome at a unique cell level in naive Biomphalaria glabrata snails. We were able to demonstrate the presence of 7 hemocyte transcriptomic populations defined by the expression of specific marker genes. As a result, scRNAseq approach showed a high heterogeneity within hemocytes, but provides a detailed description of the different hemocyte transcriptomic populations in B. glabrata supported by distinct cellular functions and lineage trajectory. As a main result, scRNAseq revealed the 3 main population as a super-group of hemocyte diversity but, on the contrary, a great hemocytes plasticity with a probable capacity of hemocytes to engage to different activation pathways. This work opens a new field of research to understand the role of hemocytes particularly in response to pathogens, and towards S. mansoni parasites.
Published: 2022

8. Major transcriptomic, epigenetic and metabolic changes underlie the pluripotency continuum in rabbit preimplantation embryos

Author: Wilhelm Bouchereau, Luc Jouneau, Catherine Archilla, Irène Aksoy, Anais Moulin, Nathalie Daniel, Nathalie Peynot, Sophie Calderari, Thierry Joly, Murielle Godet, Yan Jaszczyszyn, Marine Pratlong, Dany Severac, Pierre Savatier, Véronique Duranthon, Marielle Afanassieff, Nathalie Beaujean, Institut cellule souche et cerveau / Stem Cell and Brain Research Institute (SBRI), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Biologie de la Reproduction, Environnement, Epigénétique & Développement (BREED), École nationale vétérinaire - Alfort (ENVA)-Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Université Paris-Saclay-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Interactions Cellules Environnement - UR (ICE), VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS), Isara, Cardiovasculaire, métabolisme, diabétologie et nutrition (CarMeN), Université de Lyon-Université de Lyon-Hospices Civils de Lyon (HCL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Institut de Biologie Intégrative de la Cellule (I2BC), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS), Institut de Génomique Fonctionnelle - Montpellier GenomiX (IGF MGX), Institut de Génomique Fonctionnelle (IGF), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM)-BioCampus (BCM), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM), Unité sous contrat plate-forme biotechnologique de cellules souches plate-forme PrimaStem, Institut National de la Recherche Agronomique (INRA)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Institut cellule souche et cerveau / Stem Cell and Brain Research Institute (U1208 Inserm - UCBL1 / SBRI - USC 1361 INRAE), Institut méditerranéen d'océanologie (MIO), and Institut de Recherche pour le Développement (IRD)-Aix Marseille Université (AMU)-Institut national des sciences de l'Univers (INSU - CNRS)-Université de Toulon (UTLN)-Centre National de la Recherche Scientifique (CNRS)
Subjects: Pluripotent Stem Cells, Embryo transcriptome, Pluripotency continuum, Epigenesis, Genetic, Single-cell RNAseq, Mice, Blastocyst, Rabbit preimplantation embryo, Animals, Rabbits, Naive pluripotency, Transcriptome, Molecular Biology, [SDV.BDD]Life Sciences [q-bio]/Development Biology, Germ Layers, Developmental Biology
Abstract: Despite the growing interest in the rabbit model for developmental and stem cell biology, the characterization of embryos at the molecular level is still poorly documented. We conducted a transcriptome analysis of rabbit preimplantation embryos from E2.7 (morula stage) to E6.6 (early primitive streak stage) using bulk and single-cell RNA-sequencing. In parallel, we studied oxidative phosphorylation and glycolysis, and analysed active and repressive epigenetic modifications during blastocyst formation and expansion. We generated a transcriptomic, epigenetic and metabolic map of the pluripotency continuum in rabbit preimplantation embryos, and identified novel markers of naive pluripotency that might be instrumental for deriving naive pluripotent stem cell lines. Although the rabbit is evolutionarily closer to mice than to primates, we found that the transcriptome of rabbit epiblast cells shares common features with those of humans and non-human primates.
Published: 2022

9. PUCHI represses early meristem formation in developing lateral roots of Arabidopsis thaliana

Author: Bellande, Kevin, Trinh, Duy-Chi, Gonzalez, Anne-Alicia, Dubois, Emeric, Petitot, Anne-Sophie, Lucas, Mikaël, Champion, Antony, Gantet, Pascal, Laplaze, Laurent, Guyomarc’h, Soazig, Diversité, adaptation, développement des plantes (UMR DIADE), Centre de Coopération Internationale en Recherche Agronomique pour le Développement (Cirad)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD [France-Sud])-Université de Montpellier (UM), Université de Montpellier (UM), Institut de Génomique Fonctionnelle - Montpellier GenomiX (IGF MGX), Institut de Génomique Fonctionnelle (IGF), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM)-BioCampus (BCM), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), ROSSI, Sabine, Reproduction et développement des plantes (RDP), École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Université Montpellier 1 (UM1)-Université Montpellier 2 - Sciences et Techniques (UM2)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Montpellier 1 (UM1)-Université Montpellier 2 - Sciences et Techniques (UM2)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), and ANR-17-CE13-0004,NewRoot,Propriétés du réseau de gènes contrôlant la formation des nouvelles racines latérales chez les plantes(2017)
Subjects: [SDE] Environmental Sciences, patterning, PLETHORA, Indoleacetic Acids, Arabidopsis Proteins, organogenesis, Arabidopsis, PUCHI, Plant Roots, meristem, lateral root development, cytokinin, Gene Expression Regulation, Plant, [SDE]Environmental Sciences, auxin, Transcription Factors
Abstract: International audience; Lateral root organogenesis is a key process in the development of a plant’s root system and its adaptation to the environment. During lateral root formation, an early phase of cell proliferation first produces a four-cell-layered primordium, and only from this stage onwards is a root meristem-like structure, expressing root stem cell niche marker genes, being established in the developing organ. Previous studies reported that the gene regulatory network controlling lateral root formation is organized into two subnetworks whose mutual inhibition may contribute to organ patterning. PUCHI encodes an AP2/ERF transcription factor expressed early during lateral root primordium development and required for correct lateral root formation. To dissect the molecular events occurring during this early phase, we generated time-series transcriptomic datasets profiling lateral root development in puchi-1 mutants and wild types. Transcriptomic and reporter analyses revealed that meristem-related genes were expressed ectopically at early stages of lateral root formation in puchi-1 mutants. We conclude that, consistent with the inhibition of genetic modules contributing to lateral root development, PUCHI represses ectopic establishment of meristematic cell identities at early stages of organ development. These findings shed light on gene network properties that orchestrate correct timing and patterning during lateral root formation.
Published: 2022

10. Molecular complexity and gene expression controlling cell turnover during a digestive cycle of carnivorous sponge Lycopodina hypogea

Author: Emilie Le Goff, Camille Martinand-Mari, Khalid Belkhir, Jean Vacelet, Sabine Nidelet, Nelly Godefroy, Stephen Baghdiguian, Institut des Sciences de l'Evolution de Montpellier (UMR ISEM), Centre de Coopération Internationale en Recherche Agronomique pour le Développement (Cirad)-École Pratique des Hautes Études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut de recherche pour le développement [IRD] : UR226-Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM), Institut méditerranéen de biodiversité et d'écologie marine et continentale (IMBE), Avignon Université (AU)-Aix Marseille Université (AMU)-Institut de recherche pour le développement [IRD] : UMR237-Centre National de la Recherche Scientifique (CNRS), Institut de Génomique Fonctionnelle - Montpellier GenomiX (IGF MGX), Institut de Génomique Fonctionnelle (IGF), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM)-BioCampus (BCM), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre de Biologie pour la Gestion des Populations (UMR CBGP), Centre de Coopération Internationale en Recherche Agronomique pour le Développement (Cirad)-Institut de Recherche pour le Développement (IRD [France-Sud])-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Institut Agro Montpellier, Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro)-Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro)-Université de Montpellier (UM), Both the MGX (member of the national infrastructure France-Genomics) and the imaging facility MRI (member of the national infrastructure France-BioImaging) platforms were supported by the French National Research Agency ('Investments for the future,' ANR-10-INBS-0009 and ANR-10-INBS-0004, respectively)., ANR-10-INBS-0009,France-Génomique,Organisation et montée en puissance d'une Infrastructure Nationale de Génomique(2010), and ANR-10-INBS-0004,France-BioImaging,Développment d'une infrastructure française distribuée coordonnée(2010)
Subjects: Cell biology, Histology, Metazoa morphogenesis, Carnivorous sponge, Gene Expression, Apoptosis, [SDV.BC.BC]Life Sciences [q-bio]/Cellular Biology/Subcellular Processes [q-bio.SC], Transcriptomic analysis, Carnivory, Pathology and Forensic Medicine, [SDV.BA.ZI]Life Sciences [q-bio]/Animal biology/Invertebrate Zoology, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], Animals, Homeostasis
Abstract: International audience; Lycopodina hypogea is a carnivorous sponge that tolerates laboratory husbandry very well. During a digestion cycle, performed without any digestive cavity, this species undergoes spectacular morphological changes leading to a total regression of long filaments that ensure the capture of prey and their reformation at the end of the cycle. This phenomenon is a unique opportunity to analyze the molecular and cellular determinants that ensure digestion in the sister group of all other metazoans. Using differential transcriptomic analysis coupled with cell biology studies of proliferation, differentiation, and programmed cell deaths (i.e., autophagy and the destructive/constructive function of apoptosis), we demonstrate that the molecular and cellular actors that ensure digestive homeostasis in a sister group of all remaining animals are similar in variety and complexity to those controlling tissue homeostasis in higher vertebrates. During a digestion cycle, most of these actors are finely tuned in a coordinated manner. Our data benefits from complementary approaches coupling in silico and cell biology studies and demonstrate that the nutritive function is provided by the coordination of molecular network that impacts the cells turnover in the entire organism.
Published: 2022

11. SUMOylation controls the rapid transcriptional reprogramming induced by anthracyclines in Acute Myeloid Leukemias

Author: Mathias Boulanger, Chamseddine Kifagi, Marko Ristic, Ludovic Gabellier, Denis Tempé, Jon-Otti Sigurdsson, Tony Kaoma, Charlotte Andrieu-Soler, Thierry Forné, Eric Soler, Yosr Hicheri, Elise Gueret, Laurent Vallar, Jesper V Olsen, Guillaume Cartron, Marc Piechaczyk, Guillaume Bossis, Institut de Génétique Moléculaire de Montpellier (IGMM), Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), University of Copenhagen = Københavns Universitet (UCPH), Luxembourg Institute of Health (LIH), Institut de Génomique Fonctionnelle - Montpellier GenomiX (IGF MGX), Institut de Génomique Fonctionnelle (IGF), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM)-BioCampus (BCM), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Département d'Hématologie [CHU de Montpellier], Centre Hospitalier Universitaire de Montpellier (CHU Montpellier ), and bossis, guillaume
Subjects: [SDV] Life Sciences [q-bio], [SDV]Life Sciences [q-bio]
Abstract: Genotoxicants have been used for decades as front-line therapies against cancer on the basis of their DNA-damaging actions. However, some of their non-DNA-damaging effects are also instrumental for killing dividing cells. We report here that the anthracycline Daunorubicin (DNR), one of the main drugs used to treat Acute Myeloid Leukemia (AML), induces broad transcriptional changes in AML cells before cell death induction. The regulated genes are particularly enriched in genes controlling cell proliferation and death, as well as inflammation and immunity. These transcriptional changes are preceded by DNR-dependent deSUMOylation of chromatin proteins, which limits both the positive and negative effects of DNR on transcription. Quantitative proteomics shows that proteins that are deSUMOylated in response to DNR are mostly transcription factors, transcriptional co-regulators and chromatin organizers. Among them, the CCCTC-binding factor CTCF is highly enriched at SUMO-binding sites found in cis-regulatory regions. This is notably the case at the promoter of the DNR-induced NFKB2 gene. Its induction is preceded by a SUMO-dependent reconfiguration of chromatin loops engaging its CTCF- and SUMO-bound promoter with distal cis-regulatory regions. Altogether, our work suggests that one of the earliest effects of DNR in AML cells is a SUMO-dependent transcriptional reprogramming.
Published: 2022

12. FishmiRNA: An Evolutionarily Supported MicroRNA Annotation and Expression Database for Ray-Finned Fishes

Author: Thomas Desvignes, Philippe Bardou, Jérôme Montfort, Jason Sydes, Cervin Guyomar, Simon George, John H Postlethwait, Julien Bobe, Girard, Agnès, APPEL À PROJETS GÉNÉRIQUE 2018 - Elucider les bases cellulaires de la fécondité chez le poisson : dynamique et régulation de l'ovogenèse chez le medaka - - DynaMO2018 - ANR-18-CE20-0004 - AAPG2018 - VALID, Organisation et montée en puissance d'une Infrastructure Nationale de Génomique - - France-Génomique2010 - ANR-10-INBS-0009 - INBS - VALID, University of Oregon [Eugene], Système d'Information des GENomes des Animaux d'Elevage (SIGENAE), Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Laboratoire de Physiologie et Génomique des Poissons (LPGP), Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique )-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Institut de Génomique Fonctionnelle - Montpellier GenomiX (IGF MGX), Institut de Génomique Fonctionnelle (IGF), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM)-BioCampus (BCM), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), This work was supported by the National Institutes of Health (grant numbers NIH R24 OD011199, NIH 5R01 OD011116, and NIH R01 GM085318 to JHP), the National Science Foundation Office of Polar Program (NSF OPP-1543383 to JHP and TD), and the Agence Nationale de la Recherche (ANR-18-CE20-0004 to JB). This work benefited from access to the University of Oregon high performance computer, Talapas. MGX acknowledges financial support from France Génomique National infrastructure, funded as part of 'Investissement d'Avenir' program managed by Agence National pour la Recherche (ANR-10-INBS-09)., ANR-18-CE20-0004,DynaMO,Elucider les bases cellulaires de la fécondité chez le poisson : dynamique et régulation de l'ovogenèse chez le medaka(2018), and ANR-10-INBS-0009,France-Génomique,Organisation et montée en puissance d'une Infrastructure Nationale de Génomique(2010)
Subjects: [INFO.INFO-DB]Computer Science [cs]/Databases [cs.DB], Teleost, [SDV]Life Sciences [q-bio], non-coding RNA, Fishes, bowfin Amia calva, Holostei, [SDV] Life Sciences [q-bio], Whole Genome Duplication, MicroRNAs, actinopterygian, Genetics, [INFO.INFO-DB] Computer Science [cs]/Databases [cs.DB], Animals, Molecular Biology, Ecology, Evolution, Behavior and Systematics
Abstract: MicroRNAs (miRNAs) are important post-transcriptional regulators of gene expression involved in countless biological processes and are widely studied across metazoans. Although miRNA research continues to grow, the large community of fish miRNA researchers lacks exhaustive resources consistent among species. To fill this gap, we developed FishmiRNA, an evolutionarily supported miRNA annotation and expression database for ray-finned fishes: www.fishmirna.org. The self-explanatory database contains detailed, manually curated miRNA annotations with orthology relationships rigorously established by sequence similarity and conserved syntenies, and expression data provided for each detected mature miRNA. In just few clicks, users can download the annotation and expression database in several convenient formats either in its entirety or a subset. Simple filters and Blast search options also permit the simultaneous exploration and visual comparison of expression data for up to any ten mature miRNAs across species and organs. FishmiRNA was specifically designed for ease of use to reach a wide audience.
Published: 2022

13. Transcriptional differences between the two host strains of Spodoptera frugiperda (Lepidoptera: Noctuidae)

Author: Marion Orsucci, Yves Moné, Philippe Audiot, Sylvie Gimenez, Sandra Nhim, Rima Naït-Saïdi, Marie Frayssinet, Guillaume Dumont, Jean-Paul Boudon, Marin Vabre, Stéphanie Rialle, Rachid Koual, Gael J. Kergoat, Rodney N. Nagoshi, Robert L. Meagher, Emmanuelle d’Alençon, Nicolas Nègre, Centre de Biologie pour la Gestion des Populations (UMR CBGP), Centre de Coopération Internationale en Recherche Agronomique pour le Développement (Cirad)-Institut de Recherche pour le Développement (IRD [France-Sud])-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Institut Agro Montpellier, Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro)-Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro)-Université de Montpellier (UM), Diversité, Génomes & Interactions Microorganismes - Insectes [Montpellier] (DGIMI), Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Université de Montpellier (UM), Plant Biology, Linnean Centre for Plant Biology, Uppsala BioCentre, Swedish University of Agricultural Sciences (SLU), Drexel University College of Medicine, DIASCOPE, Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Institut de Génomique Fonctionnelle - Montpellier GenomiX (IGF MGX), Institut de Génomique Fonctionnelle (IGF), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM)-BioCampus (BCM), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), USDA/ARS, and USDA-ARS : Agricultural Research Service
Subjects: [SDV]Life Sciences [q-bio]
Abstract: International audience; Spodoptera frugiperda, the fall armyworm (FAW), is an important agricultural pest in the Americas and an emerging pest in sub-Saharan Africa, India, East-Asia and Australia, causing damage to major crops such as corn, sorghum and soybean. While FAW larvae are considered polyphagous, differences in diet preference have been described between two genetic variants: the corn strain (sf-C) and the rice strain (sf-R). These two strains are sometimes considered as distinct species, raising the hypothesis that host plant specialization might have driven their divergence. To test this hypothesis, we first performed controlled reciprocal transplant (RT) experiments to address the impact of plant diet on several traits linked to the fitness of the sf-C and sf-R strains. The phenotypical data suggest that sf-C is specialized to corn. We then used RNA-Se to identify constitutive transcriptional differences between strains, regardless of diet, in laboratory as well as in natural populations. We found that variations in mitochondrial transcription levels are among the most substantial and consistent differences between the two strains. Since mitochondrial genotypes also vary between the strains, we believe the mitochondria may have a significant role in driving strain divergence.
Published: 2022

14. Divergence of olfactory receptors associated with the evolution of assortative mating and reproductive isolation in mice

Author: Carole M. Smadja, Etienne Loire, Pierre Caminade, Dany Severac, Mathieu Gautier, Guila Ganem, Institut des Sciences de l'Evolution de Montpellier (UMR ISEM), Centre de Coopération Internationale en Recherche Agronomique pour le Développement (Cirad)-École Pratique des Hautes Études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut de recherche pour le développement [IRD] : UR226-Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM), Animal, Santé, Territoires, Risques et Ecosystèmes (UMR ASTRE), Centre de Coopération Internationale en Recherche Agronomique pour le Développement (Cirad)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Institut de Génomique Fonctionnelle - Montpellier GenomiX (IGF MGX), Institut de Génomique Fonctionnelle (IGF), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM)-BioCampus (BCM), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre de Biologie pour la Gestion des Populations (UMR CBGP), Centre de Coopération Internationale en Recherche Agronomique pour le Développement (Cirad)-Institut de Recherche pour le Développement (IRD [France-Sud])-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Institut Agro Montpellier, Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro)-Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro)-Université de Montpellier (UM), Département Systèmes Biologiques (Cirad-BIOS), Centre de Coopération Internationale en Recherche Agronomique pour le Développement (Cirad), BioCampus (BCM), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM), This work was supported by the European Union’s Seventh Framework Programme [FP7/2007-2013] –Marie Curie European Reintegration Grant (ERG), under Grant agreement n° PERG06-GA-2009-251008, as well as from the Agence Nationale pour la Recherche (ANR) under Grant agreement n° ANR-10-BLAN-1714ASSORTMATE., ANR-10-BLAN-1714,ASSORTMATE,Spéciation adaptative: approche intégrative chez la souris.(2010), European Project: 251008,EC:FP7:PEOPLE,FP7-PEOPLE-2009-RG,SPECIATIONGENOMICS(2011), Centre de Coopération Internationale en Recherche Agronomique pour le Développement (Cirad)-École pratique des hautes études (EPHE), and SMADJA, Carole
Subjects: reinforcement, speciation, [SDV.BID.EVO]Life Sciences [q-bio]/Biodiversity/Populations and Evolution [q-bio.PE], [SDV.BID.EVO] Life Sciences [q-bio]/Biodiversity/Populations and Evolution [q-bio.PE], genomics, Mus musculus, mammals, mate choice, behaviour, olfaction
Abstract: This version of the article has been peer-reviewed and recommended by Peer Community in Evolutionary Biology (https://peercommunityjournal.org/item/10.24072/pcjournal.190.pdf).Raw mapping files (BAM files) and metadata have been uploaded to the Short Read Archive (SRA, NCBI) under the bioproject ID PRJNA603262 (https://www.ncbi.nlm.nih.gov/bioproject/PRJNA603262/).Custom scripts produced for data analysis are deposited in Zenodo (https://doi.org/10.5281/zenodo.7225771).; Deciphering the genetic bases of behavioural traits is essential to understanding how they evolve and contribute to adaptation and biological diversification, but it remains a substantial challenge, especially for behavioural traits with polygenic architectures. In this study, we developed a population genomics approach coupled with functional predictions to address the evolution and genetic basis of olfactory-based assortative mate preferences in the house mouse, suspected tohave evolved as a response to selection against hybridisation. We used whole genome resequencing data and the C2 statistic of the program BAYPASS, which contrasts allele frequencies corrected for population structure, to characterize genetic differentiation between sets of populations with strong contrast in behaviour (expressing or not assortative mate preferences) and we identified some regions of the genome showing the expected significant and consistentassociation with behavioural divergence. A series of Olfactory and Vomeronasal Receptor genes, among the most differentiated genomic regions and in line with functional predictions, stand out as the prime candidates underlying this olfactory-based behavioural divergence. These genes form large gene clusters in the genome, with two main candidate clusters extending up to 1.8 Mb. Variant analyses indicate a potential dual role of regulatory and protein-coding changes in theevolution of choosiness. This study shows that combining expectations on the genomic patterns of divergence with functional expectations represents a promising route to unravelling the genetic architecture of complex trait variation and provides novel insights into the role of olfactory and vomeronasal receptors in mammal adaptation and speciation.
Published: 2022

15. Assessing the Impact of Persistent HIV Infection on Innate Lymphoid Cells Using In Vitro Models

Author: Aude Boulay, Sara Trabanelli, Stéphanie Boireau, Myriam Boyer-Clavel, Sébastien Nisole, Pedro Romero, Camilla Jandus, Anne-Sophie Beignon, Nathalie J. Arhel, Institut de Recherche en Infectiologie de Montpellier (IRIM), Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM), Université de Genève = University of Geneva (UNIGE), Ludwig Institute for Cancer Research, Montpellier Ressources Imagerie, Biocampus, CNRS, INSERM, Universite Montpellier, Montpellier, France, BioCampus (BCM), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM), Université de Lausanne = University of Lausanne (UNIL), Immunologie des maladies virales, auto-immunes, hématologiques et bactériennes (IMVA-HB), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay, Infectious Diseases Models for Innovative Therapies (IDMIT), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay, This work was supported by the Montage de Reseaux Scientifiques Européens ou Internationaux grant (N.J.A.) from the Agence Nationale de la Recherche , France, Sidaction grant for the salary of A.B., and by the Institut des sciences biologiques du Centre national de la recherche scientifique, and The Swiss Cancer League (KFS-4404-02-2018)
Subjects: [SDV]Life Sciences [q-bio], [SDV.MP.VIR]Life Sciences [q-bio]/Microbiology and Parasitology/Virology, Immunology, Immunology and Allergy, General Medicine, [SDV.IMM.II]Life Sciences [q-bio]/Immunology/Innate immunity
Abstract: Pathogens that persist in their host induce immune dysfunctions even in the absence of detectable replication. To better understand the phenotypic and functional changes that persistent infections induce in sentinel innate immune cells, we developed human PBMC-based HIV models of persistent infection. Autologous nonactivated PBMCs were cocultured with chronically infected, acutely infected, or uninfected cells and were then analyzed by unsupervised high-dimensional flow cytometry. Using this approach, we identified prevalent patterns of innate immune dysfunctions associated with persistent HIV infections that at least in part mirror immune dysfunctions observed in patients. In one or more models of chronic infection, bystander CD16+ NK cells expressing markers of activation, such as CD94, CD45RO, CD62L, CD69, CD25, and immune checkpoints PD1, Tim3, TIGIT, NKG2A and Lag3, were significantly reduced. Conversely, helper ILC subsets expressing PDL1/PDL2 were significantly enriched in chronic infection compared with either uninfected or acute infection, suggesting that chronic HIV-1 infection was associated with an inhibitory environment for bystander ILC and NK subsets. The cell-based models of persistent infection that we describe here provide versatile tools to explore the molecular mechanisms of these immune dysfunctions and unveil the contribution of innate immunity in sustaining pathogen persistence.
Published: 2023

16. Multivariate Analysis of RNA Chemistry Marks Uncovers Epitranscriptomics-Based Biomarker Signature for Adult Diffuse Glioma Diagnostics

Author: S. Relier, A. Amalric, A. Attina, I.B. Koumare, V. Rigau, F. Burel Vandenbos, D. Fontaine, M. Baroncini, J.P. Hugnot, H. Duffau, L. Bauchet, C. Hirtz, E. Rivals, A. David, Gouat, Isabelle, Institut de Génomique Fonctionnelle (IGF), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM), Plateforme de Protéomique Clinique de Montpellier (PPC), BioCampus (BCM), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM), Cellules Souches, Plasticité Cellulaire, Médecine Régénératrice et Immunothérapies (IRMB), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Service de Neurochirurgie [Montpellier], Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-CHU Gui de Chauliac [Montpellier], Hôpital Gabriel Touré [Mali], Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Centre Hospitalier Universitaire de Nice (CHU Nice), Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Méthodes et Algorithmes pour la Bioinformatique (MAB), Laboratoire d'Informatique de Robotique et de Microélectronique de Montpellier (LIRMM), and Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM)
Subjects: Proteomics, [SDV.BIBS] Life Sciences [q-bio]/Quantitative Methods [q-bio.QM], Multivariate Analysis, Humans, Metabolomics, RNA, Glioma, [SDV.BIBS]Life Sciences [q-bio]/Quantitative Methods [q-bio.QM], Biomarkers, Analytical Chemistry
Abstract: International audience; One of the main challenges in cancer management relates to the discovery of reliable biomarkers, which could guide decision-making and predict treatment outcome. In particular, the rise and democratization of high-throughput molecular profiling technologies bolstered the discovery of "biomarker signatures" that could maximize the prediction performance. Such an approach was largely employed from diverse OMICs data (i.e., genomics, transcriptomics, proteomics, metabolomics) but not from epitranscriptomics, which encompasses more than 100 biochemical modifications driving the post-transcriptional fate of RNA: stability, splicing, storage, and translation. We and others have studied chemical marks in isolation and associated them with cancer evolution, adaptation, as well as the response to conventional therapy. In this study, we have designed a unique pipeline combining multiplex analysis of the epitranscriptomic landscape by high-performance liquid chromatography coupled to tandem mass spectrometry with statistical multivariate analysis and machine learning approaches in order to identify biomarker signatures that could guide precision medicine and improve disease diagnosis. We applied this approach to analyze a cohort of adult diffuse glioma patients and demonstrate the existence of an "epitranscriptomics-based signature" that permits glioma grades to be discriminated and predicted with unmet accuracy. This study demonstrates that epitranscriptomics (co)evolves along cancer progression and opens new prospects in the field of omics molecular profiling and personalized medicine.
Published: 2022

17. A simulated marine heatwave impacts European sea bass sperm quantity, but not quality

Author: Benjamin Geffroy, Leydy Sandoval‐Vargas, Myriam Boyer‐Clavel, Maritza Pérez‐Atehortúa, Stephane Lallement, Iván Valdebenito Isler, MARine Biodiversity Exploitation and Conservation (UMR MARBEC), Institut de Recherche pour le Développement (IRD)-Institut Français de Recherche pour l'Exploitation de la Mer (IFREMER)-Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM), Montpellier Ressources Imagerie, Biocampus, CNRS, INSERM, Universite Montpellier, Montpellier, France, BioCampus (BCM), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM), and Institut Français de Recherche pour l'Exploitation de la Mer (IFREMER)
Subjects: [SDE.MCG]Environmental Sciences/Global Changes, [SDE.BE]Environmental Sciences/Biodiversity and Ecology, Aquatic Science, Ecology, Evolution, Behavior and Systematics
Abstract: International audience; Rapid environmental changes will be the major challenge that most biota will have to deal with in the near future. Extreme events, such as marine heatwaves, are becoming more frequent and could be spatially uniform at a regional scale for a relatively long period of time. To date, most research studies on heatwaves have focused on sessile organisms, but these extreme events can also impact mobile species. Here, a 3-week marine heatwave was simulated to investigate its effects on the male reproductive performance of a Mediterranean Sea emblematic species, the European sea bass Dicentrarchus labrax. Males from the control condition (c. 13°C) produced significantly more sperm than those exposed to a relatively warm thermal treatment (c. 16°C). Nonetheless, neither the percentage of motile spermatozoa nor most of the other sperm motility parameters were significantly affected by the rearing temperature over the whole period. Overall, the results of this study suggest only moderated effects of a potential winter heatwave on the reproductive performance of male European sea bass.
Published: 2023

18. Functional analyses of phosphatidylserine/PI(4)P exchangers with diverse lipid species and membrane contexts reveal unanticipated rules on lipid transfer

Author: Maud Magdeleine, Nicolas Fuggetta, Nicolas-Frédéric Lipp, Vanessa Delfosse, William Bourguet, Guillaume Drin, Souade Ikhlef, Institut de pharmacologie moléculaire et cellulaire (IPMC), Centre National de la Recherche Scientifique (CNRS)-Université Nice Sophia Antipolis (... - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Université Côte d'Azur (UCA), Centre de Biochimie Structurale [Montpellier] (CBS), Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM), Malbec, Odile, Université Nice Sophia Antipolis (1965 - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Centre National de la Recherche Scientifique (CNRS)-Université Côte d'Azur (UCA), and Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS)
Subjects: Physiology, QH301-705.5, [SDV]Life Sciences [q-bio], Plant Science, Phosphatidylserines, Saccharomyces cerevisiae, Biology, Phosphoinositide, Endoplasmic Reticulum, Ligands, General Biochemistry, Genetics and Molecular Biology, Fluorescence, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Structural Biology, Organelle, Pi, Humans, Biology (General), Phosphatidylserine, Ecology, Evolution, Behavior and Systematics, Lipid Transport, 030304 developmental biology, 0303 health sciences, Degree of unsaturation, Endoplasmic reticulum, Cell Membrane, Cell Biology, Lipid transport, [SDV] Life Sciences [q-bio], Sterols, Kinetics, Membrane, chemistry, Biophysics, General Agricultural and Biological Sciences, Plant lipid transfer proteins, 030217 neurology & neurosurgery, Developmental Biology, Biotechnology, Research Article, Plasma membrane
Abstract: Background Lipid species are accurately distributed in the eukaryotic cell so that organelle and plasma membranes have an adequate lipid composition to support numerous cellular functions. In the plasma membrane, a precise regulation of the level of lipids such as phosphatidylserine, PI(4)P, and PI(4,5)P2, is critical for maintaining the signaling competence of the cell. Several lipid transfer proteins of the ORP/Osh family contribute to this fine-tuning by delivering PS, synthesized in the endoplasmic reticulum, to the plasma membrane in exchange for PI(4)P. To get insights into the role of these PS/PI(4)P exchangers in regulating plasma membrane features, we question how they selectively recognize and transfer lipid ligands with different acyl chains, whether these proteins exchange PS exclusively for PI(4)P or additionally for PI(4,5)P2, and how sterol abundance in the plasma membrane impacts their activity. Results We measured in vitro how the yeast Osh6p and human ORP8 transported PS and PI(4)P subspecies of diverse length and unsaturation degree between membranes by fluorescence-based assays. We established that the exchange activity of Osh6p and ORP8 strongly depends on whether these ligands are saturated or not, and is high with representative cellular PS and PI(4)P subspecies. Unexpectedly, we found that the speed at which these proteins individually transfer lipid ligands between membranes is inversely related to their affinity for them and that high-affinity ligands must be exchanged to be transferred more rapidly. Next we determined that Osh6p and ORP8 cannot use PI(4,5)P2 for exchange processes, because it is a low-affinity ligand, and do not transfer more PS into sterol-rich membranes. Conclusions Our study provides new insights into PS/PI(4)P exchangers by indicating the degree to which they can regulate the acyl chain composition of the PM, and how they control PM phosphoinositide levels. Moreover, we establish general rules on how the activity of lipid transfer proteins relates to their affinity for ligands.
Published: 2021

19. Structure and mechanics of the human Nuclear Pore Complex basket

Author: Anthony Vial, Luca Costa, Patrice Dosset, Pietro Rosso, Gaëlle Boutières, Orestis Faklaris, Heiko Haschke, Pierre-Emmanuel Milhiet, Christine M. Doucet, Centre de Biologie Structurale [Montpellier] (CBS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM), Montpellier Ressources Imagerie, Biocampus, CNRS, INSERM, Universite Montpellier, Montpellier, France, BioCampus (BCM), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM), Bruker, and DOUCET, Christine
Subjects: [SDV] Life Sciences [q-bio], [SDV]Life Sciences [q-bio]
Abstract: Nuclear pore complexes (NPCs) are the only gateways between the nucleus and cytoplasm in eukaryotic cells. They restrict free diffusion to molecules below 5 nm while facilitating the active transport of selected cargoes, sometimes as large as the pore itself. This versatility implies an important pore plasticity. Recently, cryo-EM and AI-based protein modeling revealed with acute precision how most NPC constituents are arranged. But the basket, a fish trap-like structure capping the nucleoplasmic side of the pore, remains the missing piece in this puzzle. Here by Atomic Force Microscopy (AFM) coupled to Single Molecule Localization Microscopy (SMLM) we revealed that the basket is very soft and explores a large conformational landscape: apart from its canonical shape, it dives into the central pore channel or opens, with filaments reaching to the pore sides. Our observations enlighten how this structure can adapt and let morphologically diverse cargoes shuttling through NPCs.
Published: 2022

20. Allosteric modulators enhance agonist efficacy by increasing the residence time of a GPCR in the active state

Author: Emmanuel Margeat, Robert B. Quast, Anne-Marinette Cao, Philippe Rondard, Fataneh Fatemi, Jean-Philippe Pin, Centre de Biochimie Structurale [Montpellier] (CBS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Ecole Polytechnique Fédérale de Lausanne (EPFL), Shahid Beheshti University, Institut de Génomique Fonctionnelle (IGF), Centre National de la Recherche Scientifique (CNRS)-Université Montpellier 2 - Sciences et Techniques (UM2)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Montpellier 1 (UM1)-Université de Montpellier (UM), Guerineau, Nathalie C., Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Montpellier (UM)-Université Montpellier 1 (UM1)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Montpellier 2 - Sciences et Techniques (UM2)-Centre National de la Recherche Scientifique (CNRS), and Margeat, Emmanuel
Subjects: [SDV.BIO]Life Sciences [q-bio]/Biotechnology, Protein Conformation, cooperativity, [SDV]Life Sciences [q-bio], Gene Expression, General Physics and Astronomy, Molecular neuroscience, insights, Disaccharides, Receptors, Metabotropic Glutamate, taste, 0302 clinical medicine, G protein-coupled receptors, Glucosides, Catalytic Domain, Fluorescence Resonance Energy Transfer, Amino Acids, Receptor, Micelles, 0303 health sciences, Multidisciplinary, Chemistry, Glutamate receptor, Molecular conformation, Recombinant Proteins, Single Molecule Imaging, stabilization, 3. Good health, protein-coupled receptors, [SDV.BBM.BP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biophysics, [SDV] Life Sciences [q-bio], Transmembrane domain, Indans, single-molecule fret, Cholesterol Esters, Allosteric Site, Protein Binding, Agonist, Allosteric modulator, Octoxynol, medicine.drug_class, Science, Gi alpha subunit, Allosteric regulation, mechanism, [SDV.BBM.BP] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biophysics, Glutamic Acid, Diosgenin, Article, General Biochemistry, Genetics and Molecular Biology, Bridged Bicyclo Compounds, 03 medical and health sciences, Single-molecule biophysics, Allosteric Regulation, medicine, [SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology, Humans, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, 030304 developmental biology, G protein-coupled receptor, Biphenyl Compounds, Cell Membrane, General Chemistry, Bridged Bicyclo Compounds, Heterocyclic, [SDV.BIO] Life Sciences [q-bio]/Biotechnology, HEK293 Cells, Xanthenes, Metabotropic glutamate receptor, Biophysics, activation, Glycolipids, Protein Multimerization, 030217 neurology & neurosurgery
Abstract: Here, the authors use smFRET to assess the structural dynamics of metabotropic glutamate receptor mGlu2 and show that a positive allosteric modulator or the Gi protein stabilize mGlu2 in the glutamate-induced active state, leading to the full activation of the receptor., Much hope in drug development comes from the discovery of positive allosteric modulators (PAM) that display target subtype selectivity and act by increasing agonist potency and efficacy. How such compounds can allosterically influence agonist action remains unclear. Metabotropic glutamate receptors (mGlu) are G protein-coupled receptors that represent promising targets for brain diseases, and for which PAMs acting in the transmembrane domain have been developed. Here, we explore the effect of a PAM on the structural dynamics of mGlu2 in optimized detergent micelles using single molecule FRET at submillisecond timescales. We show that glutamate only partially stabilizes the extracellular domains in the active state. Full activation is only observed in the presence of a PAM or the G(i) protein. Our results provide important insights on the role of allosteric modulators in mGlu activation, by stabilizing the active state of a receptor that is otherwise rapidly oscillating between active and inactive states.
Published: 2021

21. The autism-associated Meis2 gene is necessary for cardiac baroreflex regulation in mice

Author: J Roussel, R Larcher, P Sicard, P Bideaux, S Richard, F Marmigère, J Thireau, MORNET, Dominique, Physiologie & médecine expérimentale du Cœur et des Muscles [U 1046] (PhyMedExp), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM), Institut des Biomolécules Max Mousseron [Pôle Chimie Balard] (IBMM), Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM)-Ecole Nationale Supérieure de Chimie de Montpellier (ENSCM), Université de Montpellier (UM), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Montpellier Ressources Imagerie, Biocampus, CNRS, INSERM, Universite Montpellier, Montpellier, France, BioCampus (BCM), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM), Institut de Génomique Fonctionnelle de Lyon (IGFL), École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Institut des Neurosciences de Montpellier (INM), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), and École normale supérieure de Lyon (ENS de Lyon)-Université Claude Bernard Lyon 1 (UCBL)
Subjects: Mice, Multidisciplinary, [SDV.MHEP.CSC]Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, Sensory Receptor Cells, Autism Spectrum Disorder, Heart Rate, [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, [SDV.NEU.NB] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, Animals, Autistic Disorder, Baroreflex, [SDV.MHEP.CSC] Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system
Abstract: Recent understanding of Autism Spectrum Disorder (ASD) showed that peripheral primary mechanosensitive neurons involved in touch sensation and central neurons affected in ASD share transcriptional regulators. Mutant mice for ASD-associated transcription factors exhibit impaired primary tactile perception, and restoring those genes specifically in primary sensory neurons rescue some of the anxiety-like behavior and social interaction defects.Interestingly, peripheral mechanosensitive sensory neurons also project to internal organs including the cardio-vascular system, and an imbalance of the cardio-vascular sympatho-vagal regulation is evidenced in ASD and intellectual disability. ASD patients have decreased vagal tone, suggesting dysfunction of sensory neurons involved in cardio-vascular sensing.In light of our previous finding that the ASD-associated Meis2 gene is necessary for normal touch neurons development and function, we investigated here if its inactivation in mouse peripheral sensory neurons also affects cardio-vascular sympatho-vagal regulation and baroreflex. Combining echocardiography, pharmacological challenge, blood pressure monitoring and heart rate variability analysis, we found that Meis2 mutant mice exhibited a blunted vagal response independently of any apparent cardiac malformation. These results suggest that defects in primary sensory neurons with mechanosensitive identity could participate in the imbalanced cardio-vascular sympatho-vagal tone found in ASD patients, reinforcing current hypotheses on the role of primary sensory neurons in the etiology of ASD.
Published: 2022

22. Single-particle tracking photoactivated localization microscopy of membrane proteins in living plant tissues

Author: Alexandre Martinière, Yvon Jaillais, Matthieu Pierre Platre, Marcelo Nollmann, Claire Burny, Vincent Bayle, Jean-Bernard Fiche, Reproduction et développement des plantes (RDP), École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Centre de Biochimie Structurale [Montpellier] (CBS), Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut für Populationsgenetik [Vienna], Veterinärmedizinische Universität Wien, Biochimie et Physiologie Moléculaire des Plantes (BPMP), Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS)-Institut national d’études supérieures agronomiques de Montpellier (Montpellier SupAgro), Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro)-Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), École normale supérieure de Lyon (ENS de Lyon)-Université Claude Bernard Lyon 1 (UCBL), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS)-Institut national d’études supérieures agronomiques de Montpellier (Montpellier SupAgro)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), ANR-18-CE13-0025,caLIPSO,Mécanismes du pattern lipidique du réseau trans-Golgien (trans-Golgi Network) et rôles dans le tri des protéines, la polarité cellulaire et le développement des plantes(2018), and ANR-19-CE20-0008,CellOsmo,Nanodomain membranaire: un role dans la signalisation osmotique(2019)
Subjects: Fluorescence-lifetime imaging microscopy, Computer science, [SDV]Life Sciences [q-bio], single particle tracking, Arabidopsis, Total internal reflection microscopy, Fluorescence correlation spectroscopy, total internal reflection fluorescence microscopy, General Biochemistry, Genetics and Molecular Biology, Diffusion, molecular diffusion, 03 medical and health sciences, 0302 clinical medicine, Plant Cells, super-resolution microscopy, Microscopy, Photoactivated localization microscopy, 030304 developmental biology, 0303 health sciences, plants, Super-resolution microscopy, sptPALM, Optical Imaging, photo-activated localization microscopy, Rho GTPase, Membrane Proteins, Fluorescence recovery after photobleaching, root, Single Molecule Imaging, Autofluorescence, Spectrometry, Fluorescence, Microscopy, Fluorescence, single molecule localization microscopy, auxin, Biological system, 030217 neurology & neurosurgery, Fluorescence Recovery After Photobleaching
Abstract: Super-resolution microscopy techniques have pushed the limit of optical imaging to unprecedented spatial resolutions. However, one of the frontiers in nanoscopy is its application to intact living organisms. Here we describe the implementation and application of super-resolution single-particle tracking photoactivated localization microscopy (sptPALM) to probe single-molecule dynamics of membrane proteins in live roots of the model plant Arabidopsis thaliana. We first discuss the advantages and limitations of sptPALM for studying the diffusion properties of membrane proteins and compare this to fluorescence recovery after photobleaching (FRAP) and fluorescence correlation spectroscopy (FCS). We describe the technical details for handling and imaging the samples for sptPALM, with a particular emphasis on the specificity of imaging plant cells, such as their thick cell walls or high degree of autofluorescence. We then provide a practical guide from data collection to image analyses. In particular, we introduce our sptPALM_viewer software and describe how to install and use it for analyzing sptPALM experiments. Finally, we report an R statistical analysis pipeline to analyze and compare sptPALM experiments. Altogether, this protocol should enable plant researchers to perform sptPALM using a benchmarked reproducible protocol. Routinely, the procedure takes 3–4 h of imaging followed by 3–4 d of image processing and data analysis. This protocol describes how to perform single-particle tracking photoactivated localization microscopy (sptPALM) of membrane proteins in living plant tissues. The procedure covers all stages, from sample preparation to data analysis.
Published: 2021

23. The diversity of molecular interactions involving intrinsically disordered proteins: A molecular modeling perspective

Author: Ilinka, Clerc, Amin, Sagar, Alessandro, Barducci, Nathalie, Sibille, Pau, Bernadó, Juan, Cortés, Équipe Robotique et InteractionS (LAAS-RIS), Laboratoire d'analyse et d'architecture des systèmes (LAAS), Université Toulouse - Jean Jaurès (UT2J)-Université Toulouse 1 Capitole (UT1), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Institut National des Sciences Appliquées - Toulouse (INSA Toulouse), Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Université Toulouse - Jean Jaurès (UT2J)-Université Toulouse 1 Capitole (UT1), Université Fédérale Toulouse Midi-Pyrénées, Centre de Biochimie Structurale [Montpellier] (CBS), Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM), ANR-17-CE11-0022,GPCteR,Mécanismes moléculaires des régions C-terminales désordonnées et fonctionnelles des RCPG et impact sur les voies de la signalisation cellulaire dépendantes de l'arrestine(2017), ANR-14-ACHN-0016,M4,Modélisation Multi-échelle des Machines bioMoléculaires(2014), ANR-19-P3IA-0004,ANITI,Artificial and Natural Intelligence Toulouse Institute(2019), Université Toulouse Capitole (UT Capitole), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National des Sciences Appliquées - Toulouse (INSA Toulouse), Institut National des Sciences Appliquées (INSA)-Université de Toulouse (UT)-Institut National des Sciences Appliquées (INSA)-Université Toulouse - Jean Jaurès (UT2J), Université de Toulouse (UT)-Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Centre National de la Recherche Scientifique (CNRS)-Institut National Polytechnique (Toulouse) (Toulouse INP), Université de Toulouse (UT)-Université Toulouse Capitole (UT Capitole), Université de Toulouse (UT), and Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS)
Subjects: [SDV.BBM.BP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biophysics, Liquid-liquid phase separation, Intrinsically disordered proteins, Molecular dynamics simulations, Molecular recognition elements, Molecular interactions, Review Article, [INFO.INFO-BI]Computer Science [cs]/Bioinformatics [q-bio.QM], [SDV.BBM.BC]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biochemistry [q-bio.BM], TP248.13-248.65, Conformational sampling, Biotechnology
Abstract: International audience; Intrinsically Disordered Proteins and Regions (IDPs/IDRs) are key components of a multitude of biological processes. Conformational malleability enables IDPs/IDRs to perform very specialized functions that cannot be accomplished by globular proteins. The functional role for most of these proteins is related to the recognition of other biomolecules to regulate biological processes or as a part of signaling pathways. Depending on the extent of disorder, the number of interacting sites and the type of partner, very different architectures for the resulting assemblies are possible. More recently, molecular condensates with liquid-like properties composed of multiple copies of IDPs and nucleic acids have been proven to regulate key processes in eukaryotic cells. The structural and kinetic details of disordered biomolecular complexes are difficult to unveil experimentally due to their inherent conformational heterogeneity. Computational approaches, alone or in combination with experimental data, have emerged as unavoidable tools to understand the functional mechanisms of this elusive type of assemblies. The level of description used, all-atom or coarse-grained, strongly depends on the size of the molecular systems and on the timescale of the investigated mechanism. In this mini-review, we describe the most relevant architectures found for molecular interactions involving IDPs/IDRs and the computational strategies applied for their investigation.
Published: 2021

24. TAT-RasGAP 317-326 kills cells by targeting inner-leaflet–enriched phospholipids

Author: Christian Widmann, Filip Stojceski, Pierre-Emmanuel Milhiet, Gabriel Ichim, Gianvito Grasso, Robyn Roth, Cédric Godefroy, Kushal Kumar Das, Andrea Danani, Marc Serulla, Tim Schober, Ana J. García-Sáez, Sergii Afonin, Mathieu Heulot, Milhiet, Pierre-Emmanuel, Université de Lausanne = University of Lausanne (UNIL), Centre de Recherche en Cancérologie de Lyon (UNICANCER/CRCL), Centre Léon Bérard [Lyon]-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Istituto Dalle Molle di Studi sull'Intelligenza Artificiale (IDSIA), Università della Svizzera italiana = University of Italian Switzerland (USI)-Scuola universitaria professionale della Svizzera italiana = University of Applied Sciences and Arts of Southern Switzerland [Manno] (SUPSI), Karlsruhe Institute of Technology (KIT), Karlsruher Institut für Technologie (KIT), Washington University School of Medicine [Saint Louis, MO], Centre de Biochimie Structurale [Montpellier] (CBS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Eberhard Karls Universität Tübingen = Eberhard Karls University of Tuebingen, University of Lausanne (UNIL), Università della Svizzera italiana = University of Italian Switzerland (USI)-Scuola universitaria professionale della Svizzera italiana [Manno] (SUPSI), Washington University School of Medecine [Saint Louis, MO], Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM), and Interfaculty Institute of Biochemistry (IFIB), University of Tübingen, 72076, Tübingen, Germany
Subjects: Phosphatidylinositol 4,5-Diphosphate, 0301 basic medicine, Programmed cell death, Necrosis, [SDV.BBM.BP] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biophysics, Peptide, CHO Cells, Phosphatidylserines, Molecular Dynamics Simulation, 03 medical and health sciences, chemistry.chemical_compound, Cricetulus, 0302 clinical medicine, Neoplasms, medicine, Animals, Humans, Nuclear Magnetic Resonance, Biomolecular, chemistry.chemical_classification, Multidisciplinary, Cell Death, Chemistry, Cell Membrane, GTPase-Activating Proteins, Phosphatidylserine, Biological Sciences, Peptide Fragments, Cell biology, Point mutant, [SDV.BBM.BP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biophysics, Microscopy, Electron, Cytosol, 030104 developmental biology, Membrane, 030220 oncology & carcinogenesis, Liposomes, Cancer cell, lipids (amino acids, peptides, and proteins), medicine.symptom, HeLa Cells
Abstract: International audience; TAT-RasGAP 317–326 is a cell-penetrating peptide-based construct with anticancer and antimicrobial activities. This peptide kills a subset of cancer cells in a manner that does not involve known programmed cell death pathways. Here we have elucidated the mode of action allowing TAT-RasGAP 317–326 to kill cells. This peptide binds and disrupts artificial membranes containing lipids typically enriched in the inner leaflet of the plasma membrane, such as phosphatidylinositol-bisphosphate (PIP 2 ) and phosphatidylserine (PS). Decreasing the amounts of PIP 2 in cells renders them more resistant to TAT-RasGAP 317–326 , while reducing the ability of cells to repair their plasma membrane makes them more sensitive to the peptide. The W317A TAT-RasGAP 317–326 point mutant, known to have impaired killing activities, has reduced abilities to bind and permeabilize PIP 2 - and PS-containing membranes and to translocate through biomembranes, presumably because of a higher propensity to adopt an α-helical state. This work shows that TAT-RasGAP 317–326 kills cells via a form of necrosis that relies on the physical disruption of the plasma membrane once the peptide targets specific phospholipids found on the cytosolic side of the plasma membrane.
Published: 2020

25. Relaxation time asymmetry in stator dynamics of the bacterial flagellar motor

Author: Jerome Dorignac, Jean-Charles Walter, Andrea Parmeggiani, María-José Franco-Oñate, Nils-Ole Walliser, Ashley L. Nord, Fred Geniet, John Palmeri, Ruben Perez-Carrasco, Department of Life Sciences, Imperial College London, Laboratoire Charles Coulomb (L2C), Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Centre de Biochimie Structurale [Montpellier] (CBS), Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM), Centre de Biologie Structurale [Montpellier] (CBS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM), and Nord, Ashley
Subjects: Stator, media_common.quotation_subject, [PHYS.PHYS.PHYS-BIO-PH]Physics [physics]/Physics [physics]/Biological Physics [physics.bio-ph], Flagellum, 010402 general chemistry, 01 natural sciences, Asymmetry, law.invention, 03 medical and health sciences, Bacterial Proteins, law, Molecular motor, Torque, Ion channel, 030304 developmental biology, media_common, Physics, 0303 health sciences, Multidisciplinary, [PHYS.PHYS.PHYS-BIO-PH] Physics [physics]/Physics [physics]/Biological Physics [physics.bio-ph], Bacteria, Rotor (electric), Molecular Motor Proteins, Dynamics (mechanics), 0104 chemical sciences, Flagella, Biophysics
Abstract: The bacterial flagellar motor (BFM) is the membrane-embedded rotary molecular motor which turns the flagellum that provides thrust to many bacterial species. This large multimeric complex, composed of a few dozen constituent proteins, has emerged as a hallmark of dynamic subunit exchange. The stator units are inner-membrane ion channels which dynamically bind and unbind to the peptidoglycan at the rotor periphery, consuming the ion motive force (IMF) and applying torque to the rotor when bound. The dynamic exchange is known to be a function of the viscous load on the flagellum, allowing the bacterium to dynamically adapt to its local viscous environment, but the molecular mechanisms of exchange and mechanosensitivity remain to be revealed. Here, by actively perturbing the steady-state stator stoichiometry of individual motors, we reveal a stoichiometry-dependent asymmetry in stator remodeling kinetics. We interrogate the potential effect of next-neighbor interactions and local stator unit depletion and find that neither can explain the observed asymmetry. We then simulate and fit two mechanistically diverse models which recapitulate the asymmetry, finding stator assembly dynamics to be particularly well described by a two-state catch-bond mechanism.
Published: 2022

26. Rational programming of history-dependent logic in cellular populations

Author: Ana Zúñiga, Pauline Mayonove, Z. Ben Meriem, Miguel Camacho, Violaine Moreau, Pascal Hersen, Jerome Bonnet, Luca Ciandrini, Sarah Guiziou, Bodescot, Myriam, Infrastructure Française pour la Biologie Structurale Intégrée - - FRISBI2010 - ANR-10-INBS-0005 - INBS - VALID, Centre de Biochimie Structurale [Montpellier] (CBS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), University of Washington [Seattle], Matière et Systèmes Complexes (MSC (UMR_7057)), Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Laboratoire Charles Coulomb (L2C), Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Laboratoire Physico-Chimie Curie [Institut Curie] (PCC), Institut Curie [Paris]-Institut de Chimie du CNRS (INC)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Support was provided by an ERC Starting Grant 'Compucell,' the INSERM Atip-Avenir program and the Bettencourt-Schueller Foundation. S.G. was supported by a Ph.D. fellowship from the French Ministry of Research and the French Foundation for Medical Research (FRM) FDT20170437282. Z.B.M. and P.H. were supported by an ERC Consolidator grant 'Smartcells.' The CBS acknowledges support from the French Infrastructure for Integrated Structural Biology (FRISBI) ANR-10-INSB-05-01., ANR-10-INBS-0005,FRISBI,Infrastructure Française pour la Biologie Structurale Intégrée(2010), Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM), and Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP)
Subjects: Logic, Computer science, Science, Population, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, ENCODE, Article, Cell Physiological Phenomena, Workflow, Recombinases, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Biomanufacturing, education, lcsh:Science, [SDV.BC] Life Sciences [q-bio]/Cellular Biology, Gene, 030304 developmental biology, 0303 health sciences, education.field_of_study, Models, Genetic, Molecular engineering, business.industry, DNA, Modular design, Programming language, Multicellular organism, chemistry, Scalability, Synthetic Biology, lcsh:Q, Software engineering, business, Software, 030217 neurology & neurosurgery, Biotechnology
Abstract: Genetic programs operating in a history-dependent fashion are ubiquitous in nature and govern sophisticated processes such as development and differentiation. The ability to systematically and predictably encode such programs would advance the engineering of synthetic organisms and ecosystems with rich signal processing abilities. Here we implement robust, scalable history-dependent programs by distributing the computational labor across a cellular population. Our design is based on standardized recombinase-driven DNA scaffolds expressing different genes according to the order of occurrence of inputs. These multicellular computing systems are highly modular, do not require cell-cell communication channels, and any program can be built by differential composition of strains containing well-characterized logic scaffolds. We developed automated workflows that researchers can use to streamline program design and optimization. We anticipate that the history-dependent programs presented here will support many applications using cellular populations for material engineering, biomanufacturing and healthcare., Automated frameworks to systematically implement robust history-dependent genetic programs in cellular populations.
Published: 2020

27. Small-Molecule Inhibitors of Cyclophilins Block Opening of the Mitochondrial Permeability Transition Pore and Protect Mice From Hepatic Ischemia/Reperfusion Injury

Author: Muriel Gelin, Fred Allemand, Cong Trung Nguyen, Mathieu Panel, Abdelhakim Ahmed-Belkacem, Bijan Ghaleh, Rozenn Brillet, Isaac Ruiz, Julien Calderaro, Fouad Lafdil, Jean-François Guichou, Fatima Teixeira-Clerc, Didier Morin, Jean-Michel Pawlotsky, Institut Mondor de Recherche Biomédicale (IMRB), Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Centre de Biochimie Structurale [Montpellier] (CBS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), morin, didier, and Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM)
Subjects: Male, 0301 basic medicine, Isomerase activity, [SDV.MHEP.CHI] Life Sciences [q-bio]/Human health and pathology/Surgery, Ischemia, Mitochondria, Liver, [SDV.MHEP.CHI]Life Sciences [q-bio]/Human health and pathology/Surgery, Pharmacology, Mitochondrion, Mitochondrial Membrane Transport Proteins, Mouse model, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, medicine, Animals, Humans, Calcium Signaling, Enzyme Inhibitors, Inner mitochondrial membrane, Cells, Cultured, Mice, Knockout, Hepatology, Mitochondrial Permeability Transition Pore, Chemistry, Liver Diseases, MPTP, Gastroenterology, PPIF, [SDV.MHEP.HEG]Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology, medicine.disease, [SDV.MHEP.HEG] Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology, 3. Good health, PPIase activity, Mice, Inbred C57BL, Disease Models, Animal, 030104 developmental biology, Liver, Mitochondrial permeability transition pore, Cytoprotection, [SDV.SP.PHARMA] Life Sciences [q-bio]/Pharmaceutical sciences/Pharmacology, Reperfusion Injury, [SDV.SP.PHARMA]Life Sciences [q-bio]/Pharmaceutical sciences/Pharmacology, 030211 gastroenterology & hepatology, Drug, Mitochondrial Swelling, Reperfusion injury, Cyclophilin D, Signal Transduction
Abstract: International audience; Background & Aims: Hepatic ischemia-reperfusion injury is a complication of liver surgery that involves mitochondrial dysfunction resulting from mitochondrial permeability transition pore (mPTP) opening. Cyclophilin D (PPIF or CypD) is a peptidyl-prolyl cis-trans isomerase that regulates mPTP opening in the inner mitochondrial membrane. We investigated whether and how recently created small-molecule inhibitors of CypD prevent opening of the mPTP in hepatocytes and the resulting effects in cell models and livers of mice undergoing ischemia/reperfusion injuryMethods: We measured the activity of 9 small-molecule inhibitors of cyclophilins in an assay of CypD activity. The effects of the small-molecule CypD inhibitors or vehicle on mPTP opening were assessed by measuring mitochondrial swelling and calcium retention in isolated liver mitochondria from C57BL/6J (wild-type) and Ppif–/– (CypD knockout) mice and in primary mouse and human hepatocytes by fluorescence microscopy. We induced ischemia/reperfusion injury in livers of mice given a small-molecule CypD inhibitor or vehicle before and during reperfusion and collected samples of blood and liver for histologic analysis.Results: The compounds inhibited peptidyl-prolyl isomerase activity (half maximal inhibitory concentration values, 0.2–16.2 μmol/L) and, as a result, calcium-induced mitochondrial swelling, by preventing mPTP opening (half maximal inhibitory concentration values, 1.4–132 μmol/L) in a concentration-dependent manner. The most potent inhibitor (C31) bound CypD with high affinity and inhibited swelling in mitochondria from livers of wild-type and Ppif–/– mice (indicating an additional, CypD-independent effect on mPTP opening) and in primary human and mouse hepatocytes. Administration of C31 in mice with ischemia/reperfusion injury before and during reperfusion restored hepatic calcium retention capacity and oxidative phosphorylation parameters and reduced liver damage compared with vehicle.Conclusions:Recently created small-molecule inhibitors of CypD reduced calcium-induced swelling in mitochondria from mouse and human liver tissues. Administration of these compounds to mice during ischemia/reperfusion restored hepatic calcium retention capacity and oxidative phosphorylation parameters and reduced liver damage. These compounds might be developed to protect patients from ischemia/reperfusion injury after liver surgery or for other hepatic or nonhepatic disorders related to abnormal mPTP opening.
Published: 2019

28. Preparing sequencing grade RNAs from a small number of FACS-sorted larvae macrophages isolated from enzyme free dissociated zebrafish larvae

Author: Christina Begon-Pescia, Stéphanie Boireau, Myriam Boyer-Clavel, Georges Lutfalla, Mai Nguyen-Chi, LPHI - Laboratory of Pathogen Host Interactions (LPHI), Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM), Montpellier Ressources Imagerie, Biocampus, CNRS, INSERM, Universite Montpellier, Montpellier, France, BioCampus (BCM), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM), and Nguyen Chi, Mai
Subjects: FACS-sorted, Medical Laboratory Technology, Zebrafish larva, [SDV.IMM] Life Sciences [q-bio]/Immunology, RNA quality, Clinical Biochemistry, [SDV.IMM]Life Sciences [q-bio]/Immunology, Macrophages dissociation
Abstract: International audience; Macrophages are phagocytic cells from the innate immune system that are critical for tissue homeostasis and form the first line of host defense against invading pathogens. The zebrafish larva is an exquisite model to decipher the transcriptional response of macrophages after injury. We used a macrophage reporter line in which an mfap4 promoter drives the expression of a farnesylated mCherry fluorescent protein to label macrophages and we performed tissue dissociation, cell isolation by Fluorescence Activated Cell sorting and RNA preparation. The two bottlenecks are (i) the dissociation of the embryos that often relies on cell suspension steps that alter the activation status of immune cells, and (ii) obtaining high RNA integrity for gene expression analysis from a small number of isolated macrophages. Here, we describe (i) the dissociation of cells from whole Tg(mfap4:mCherry-F) zebrafish larvae using an enzyme-free and osmotically controlled buffer, (ii) the sorting of fluorescent macrophages by FACS and (iii) the preparation of high quality RNAs for meaningful gene expression analysis from a small number of isolated macrophages.•An optimized protocol in 5 steps to extract high quality RNAs from zebrafish macrophages.•A cell dissociation method using an enzyme-free and osmotically controlled buffer to prevent the alteration of macrophage activation status and limit cell mortality.•Production of high integrity RNAs from a small number of isolated macrophages.
Published: 2021

29. Discovery of a cryptic site at the interface 2 of TEAD – Towards a new family of YAP/TAZ-TEAD inhibitors

Author: Jean-François Guichou, Manon Sturbaut, Romain Magnez, Marie-Christine Chartier-Harlin, Patricia Melnyk, Martine Pugnière, Maxime Liberelle, Pasquale Sileo, Philippe Cotelle, Xavier Thuru, Muriel Gelin, Fabrice Bailly, Mathilde Coevoet, Frédéric Allemand, Lille Neurosciences & Cognition - U 1172 (LilNCog (ex-JPARC)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Institut de Recherche en Cancérologie de Montpellier (IRCM - U1194 Inserm - UM), CRLCC Val d'Aurelle - Paul Lamarque-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Cancer Heterogeneity, Plasticity and Resistance to Therapies - UMR 9020 - U 1277 (CANTHER), Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Centre National de la Recherche Scientifique (CNRS), Centre de Biochimie Structurale [Montpellier] (CBS), Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centrale Lille, This work was financially supported by grants from le Ministère de l’Education et de la Recherche and the University of Lille (M. S. and P.S.) and fundings from le Cancéropôle Nord-Ouest (Mobility Support Program for Young Researchers, M. S.). This work was also supported by the French Infrastructure for Integrated Structural Biology (FRISBI) ANR-10-INSB-05-01., ANR-10-INBS-0005,FRISBI,Infrastructure Française pour la Biologie Structurale Intégrée(2010), Lille Neurosciences & Cognition - U 1172 (LilNCog), and Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS)
Subjects: Models, Molecular, TEAD cryptic binding pocket, Hippo pathway, Antineoplastic Agents, Cell Cycle Proteins, Ligands, TEAD inhibition, 03 medical and health sciences, Structure-Activity Relationship, 0302 clinical medicine, Transcription (biology), Drug Discovery, Humans, [CHIM]Chemical Sciences, Tissue homeostasis, Binding assays, 030304 developmental biology, Cell Proliferation, Pharmacology, 0303 health sciences, Hippo signaling pathway, Dose-Response Relationship, Drug, Molecular Structure, Chemistry, Cell growth, Organic Chemistry, HEK 293 cells, TEA Domain Transcription Factors, General Medicine, Interface 2, 3. Good health, Cell biology, HEK293 Cells, 030220 oncology & carcinogenesis, Transcriptional Coactivator with PDZ-Binding Motif Proteins, Phosphorylation, Pyrazoles, Nuclear transport, Cellular model, Drug Screening Assays, Antitumor, Transcription Factors
Abstract: International audience; The Hippo pathway is involved in organ size control and tissue homeostasis by regulating cell growth, proliferation and apoptosis. It controls the phosphorylation of the transcription co-activator YAP (Yes associated protein) and TAZ (Transcriptional coactivator with PDZ-binding motif) in order to control their nuclear import and their interaction with TEAD (Transcriptional Enhanced Associated Domain). YAP, TAZ and TEADs are dysregulated in several cancers making YAP/TAZ-TEAD interaction a new emerging anti-cancer target. We report the synthesis of a set of trisubstituted pyrazoles which bind to hTEAD2 at the interface 2 revealing for the first time a cryptic pocket created by the movement of the phenol ring of Y382. Compound 6 disrupts YAP/TAZ-TEAD interaction in HEK293T cells and inhibits TEAD target genes and cell proliferation in MDA-MB-231 cells. Compound 6 is therefore the first inhibitor of YAP/TAZ-TEAD targeting interface 2. This molecule could serve with other pan-TEAD inhibitors such as interface 3 ligands, for the delineation of the relative importance of VGLL vs YAP/TAZ in a given cellular model.
Published: 2021

30. Structures of the archaerhodopsin-3 transporter reveal that disordering of internal water networks underpins receptor sensitization

Author: Carol V. Robinson, Hsin-Yung Yen, Juan F. Bada Juarez, Kin Kuan Hoi, Igor Schapiro, Danny Axford, Anthony Vial, Anthony Watts, Isabel Moraes, Suliman Adam, James M. Birch, J. Vinals, Tristan O. C. Kwan, Pierre-Emmanuel Milhiet, Peter J. Judge, Department of Biochemistry [Oxford], University of Oxford [Oxford], The Fritz Haber Research Center for Molecular Dynamics [Jerusalem], The Hebrew University of Jerusalem (HUJ), DIAMOND Light source, Diamond Light Source Limited [Didcot, UK], Harwell Science and Innovation Campus [Didcot, UK], Rutherford Appleton Laboratory, Research Complex at Harwell, Chemistry Research Laboratory [Oxford, UK], Omas therapeutics, Centre de Biochimie Structurale [Montpellier] (CBS), Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM), University of Oxford, Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), and Milhiet, Pierre-Emmanuel
Subjects: 0301 basic medicine, [SDV.BBM.BS] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Structural Biology [q-bio.BM], Science, Archaeal Proteins, Molecular Conformation, General Physics and Astronomy, Electrons, Optogenetics, Crystallography, X-Ray, General Biochemistry, Genetics and Molecular Biology, Article, 03 medical and health sciences, chemistry.chemical_compound, Computational biophysics, Membrane biophysics, 0302 clinical medicine, Isomerism, Membrane proteins, Receptor, X-ray crystallography, Membrane potential, Multidisciplinary, [SDV.BBM.BS]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Structural Biology [q-bio.BM], Membrane Transport Proteins, Water, Retinal, Hydrogen Bonding, General Chemistry, Chromophore, Lipids, 030104 developmental biology, chemistry, Biophysics, Retinaldehyde, Bacterial rhodopsins, sense organs, Protons, Ground state, Isomerization, Protein Processing, Post-Translational, 030217 neurology & neurosurgery
Abstract: Many transmembrane receptors have a desensitized state, in which they are unable to respond to external stimuli. The family of microbial rhodopsin proteins includes one such group of receptors, whose inactive or dark-adapted (DA) state is established in the prolonged absence of light. Here, we present high-resolution crystal structures of the ground (light-adapted) and DA states of Archaerhodopsin-3 (AR3), solved to 1.1 Å and 1.3 Å resolution respectively. We observe significant differences between the two states in the dynamics of water molecules that are coupled via H-bonds to the retinal Schiff Base. Supporting QM/MM calculations reveal how the DA state permits a thermodynamic equilibrium between retinal isomers to be established, and how this same change is prevented in the ground state in the absence of light. We suggest that the different arrangement of internal water networks in AR3 is responsible for the faster photocycle kinetics compared to homologs., Archaerhodopsin-3 (AR3) mutants are commonly used in optogenetics for neuron silencing and membrane voltage sensing. High-resolution crystal structures show that desensitization of the AR3 photoreceptor occurs when internal hydrogen-bonded water networks are modified in response to changes in chromophore isomerization.
Published: 2021

31. Δ133p53β isoform pro-invasive activity is regulated through an aggregation-dependent mechanism in cancer cells

Author: Gilles Gadea, Frédéric Allemand, Nikola Arsic, Sylvain de Rossi, Pierre Roux, Marina Kazantseva, Sunali Mehta, Serge Urbach, Andrey V. Kajava, Martial Séveno, Antony W. Braithwaite, Aurélie Fournet, Nathalie Sibille, Etienne Villain, Pau Bernadó, Jean-Christophe Bourdon, Tania L. Slatter, Centre de recherche en Biologie Cellulaire (CRBM), Université Montpellier 2 - Sciences et Techniques (UM2)-Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM)-Université Montpellier 1 (UM1), University of Otago [Dunedin, Nouvelle-Zélande], Université de La Réunion (UR), Cyclotron Réunion Océan Indien (CYROI), Université de La Réunion (UR)-Centre Hospitalier Universitaire de La Réunion (CHU La Réunion), Centre de Biochimie Structurale [Montpellier] (CBS), Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM), BioCampus Montpellier (BCM), Université Montpellier 1 (UM1)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Institut de Génomique Fonctionnelle (IGF), Université de Montpellier (UM)-Université Montpellier 1 (UM1)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Montpellier 2 - Sciences et Techniques (UM2)-Centre National de la Recherche Scientifique (CNRS), Ninewells Hospital and Medical School [Dundee], Institut de Biologie Computationnelle (IBC), Institut National de Recherche en Informatique et en Automatique (Inria)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Centre de recherche en Biologie cellulaire de Montpellier (CRBM), Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), BioCampus (BCM), Centre National de la Recherche Scientifique (CNRS)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Institut National de Recherche en Informatique et en Automatique (Inria)-Université de Montpellier (UM), and Prigent, Claude
Subjects: Gene isoform, Models, Molecular, Cell biology, Protein Conformation, Science, General Physics and Astronomy, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, Protein Aggregation, Pathological, General Biochemistry, Genetics and Molecular Biology, Article, 03 medical and health sciences, Mice, Protein Aggregates, 0302 clinical medicine, Cell Line, Tumor, Neoplasms, medicine, Animals, Humans, Protein Isoforms, Neoplasm Invasiveness, [SDV.BC] Life Sciences [q-bio]/Cellular Biology, 030304 developmental biology, Protein Unfolding, Cancer, Cell invasion, 0303 health sciences, Multidisciplinary, Chemistry, Mechanism (biology), General Chemistry, medicine.disease, Gene Expression Regulation, Neoplastic, 030220 oncology & carcinogenesis, Cancer cell, Mutation, MCF-7 Cells, Chaperone complex, sense organs, Tumor Suppressor Protein p53, Intracellular
Abstract: The p53 isoform, Δ133p53β, is critical in promoting cancer. Here we report that Δ133p53β activity is regulated through an aggregation-dependent mechanism. Δ133p53β aggregates were observed in cancer cells and tumour biopsies. The Δ133p53β aggregation depends on association with interacting partners including p63 family members or the CCT chaperone complex. Depletion of the CCT complex promotes accumulation of Δ133p53β aggregates and loss of Δ133p53β dependent cancer cell invasion. In contrast, association with p63 family members recruits Δ133p53β from aggregates increasing its intracellular mobility. Our study reveals novel mechanisms of cancer progression for p53 isoforms which are regulated through sequestration in aggregates and recruitment upon association with specific partners like p63 isoforms or CCT chaperone complex, that critically influence cancer cell features like EMT, migration and invasion., p53 isoform Δ133p53β is reported to promote intrinsic oncogenic functions. Here the authors show Δ133p53β is sequestered as aggregates in an inactive form, while association with interacting partners including p63 isoforms and the CCT chaperone complex promotes Δ133p53β activity, resulting in enhanced cancer cell migration and invasion.
Published: 2021

32. Stress response in dissociation and conversion disorders: A systematic review

Author: Philippe Courtet, Jorge Lopez-Castroman, Stéphane Mouchabac, Mocrane Abbar, Eric Thouvenot, Emilie Olié, Charlotte Boulet, Ismael Conejero, Centre Hospitalier Universitaire de Nîmes (CHU Nîmes), Institut de Génomique Fonctionnelle (IGF), Université de Montpellier (UM)-Université Montpellier 1 (UM1)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Montpellier 2 - Sciences et Techniques (UM2)-Centre National de la Recherche Scientifique (CNRS), Service de Psychiatrie adultes [CHU Saint-Antoine], CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute (ICM), Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Centre de Biochimie Structurale [Montpellier] (CBS), Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de psychiatrie adulte [CHU Saint-Antoine], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), and Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)
Subjects: Hypothalamo-Hypophyseal System, medicine.drug_class, Cognitive Neuroscience, [SDV]Life Sciences [q-bio], MEDLINE, Pituitary-Adrenal System, Dissociative Disorders, Autonomic Nervous System, Dissociative, Dissociation (psychology), Cortisol, Stress Disorders, Post-Traumatic, 03 medical and health sciences, Behavioral Neuroscience, 0302 clinical medicine, Psychiatric history, medicine, Humans, Dissociative disorders, Conversion disorder, Stress regulation, Autonomous nervous system, business.industry, HPA axis, medicine.disease, 030227 psychiatry, 3. Good health, Dissociative disorder, Autonomic nervous system, Neuropsychology and Physiological Psychology, Systematic review, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], medicine.symptom, business, 030217 neurology & neurosurgery, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, Clinical psychology
Abstract: International audience; Dissociative disorders (DD) and conversion disorders (CD) are frequent in general and psychiatric populations. Some evidence suggest that the hypothalamic-pituitary axis (HPA) and autonomic nervous system (ANS) are dysregulated in both disorders. We carried out a systematic review of the literature to summarize the existing knowledge on the stress response, via HPA and/or ANS, in patients with DD, CD, or dissociative symptoms. We systematically searched Medline and Web of Science using the Medical Subject Headings related to stress axis, CD, DD, and dissociative symptoms following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Results suggest that in participants without psychiatric history, high cortisol secretion is related to high dissociation scores. Conversely the stress system might be blunted in patients with post-traumatic stress disorder who develop dissociative symptoms. Stress response changes seem to be associated with the emergence and persistence of dissociative and conversion disorders. Hence, monitoring the stress response and examining closely the history of stress exposure in DD and CD should be encouraged in future larger studies.
Published: 2021

33. A Mycobacterium tuberculosis effector targets mitochondrion, controls energy metabolism and limits cytochrome c exit

Author: Marianne Martin, Angelique deVisch, Yves-Marie Boudehen, Philippe Barthe, Claude Gutierrez, Obolbek Turapov, Talip Aydogan, Laurène Heriaud, Jerome Gracy, Olivier Neyrolles, Galina V. Mukamolova, François Letourneur, Martin Cohen-Gonsaud, LPHI - Laboratory of Pathogen Host Interactions (LPHI), Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Centre de Biochimie Structurale [Montpellier] (CBS), Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM), University of Leicester, MARTIN LAVERRAT, Marianne, and Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS)
Subjects: Microbiology (medical), 0303 health sciences, biology, General Immunology and Microbiology, Ecology, 030306 microbiology, Effector, Mitochondrial intermembrane space, Physiology, Cytochrome c, [SDV]Life Sciences [q-bio], Oxidative phosphorylation, Cell Biology, Mitochondrion, 3. Good health, Cell biology, [SDV] Life Sciences [q-bio], 03 medical and health sciences, Immune system, Infectious Diseases, Apoptosis, biology.protein, Genetics, Reprogramming, 030304 developmental biology
Abstract: Host metabolism reprogramming is a key feature of Mycobacterium tuberculosis (Mtb) infection that enables the survival of this pathogen within phagocytic cells and modulates the immune response facilitating the spread of the tuberculosis disease. Here, we demonstrate that a previously uncharacterized secreted protein from Mtb, Rv1813c manipulates the host metabolism by targeting mitochondria. When expressed in eukaryotic cells, the protein is delivered to the mitochondrial intermembrane space and promotes the enhancement of host ATP production by boosting the oxidative phosphorylation metabolic pathway. Furthermore, the release of cytochrome c from mitochondria, an early apoptotic event in response to short-term oxidative stress, is delayed in Rv1813c expressing cells. This study reveals a novel class of mitochondria targeting effectors from Mtb which might participate in host cells metabolic reprogramming and apoptosis control during Mtb infections.
Published: 2021

34. A nanobody activating metabotropic glutamate receptor 4 discriminates between homo- and heterodimers

Author: Joan Font, Robert B. Quast, Patrick Chames, Jordi Haubrich, Anne Goupil-Lamy, Damien Nevoltris, Jean-Philippe Pin, Pauline Scholler, Philippe Rondard, Francine Acher, Laurent Prézeau, Institut de Génomique Fonctionnelle (IGF), Université de Montpellier (UM)-Université Montpellier 1 (UM1)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Montpellier 2 - Sciences et Techniques (UM2)-Centre National de la Recherche Scientifique (CNRS), Centre de Biochimie Structurale [Montpellier] (CBS), Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM), Dassault Systèmes, Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC), Université de Paris (UP), ANR-18-CE11-0004,DynaMuR2,Dynamique structurale d'un RCPG dimérique en molécule unique(2018), ANR-10-LABX-0053,MAbImprove,Optimization of therapeutic monoclonal antibodies development Better antibodies, better developed AND better used(2010), ANR-15-CE18-0020,nanoGluAct,Modulation de la synapse glutamatergique à l'aide de nanobodies(2015), ANR-10-INBS-0004,France-BioImaging,Développment d'une infrastructure française distribuée coordonnée(2010), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Aix Marseille Université (AMU), Université Paris Cité - UFR Sciences du Vivant [Sciences] (UPCité - UFR SDV), Université Paris Cité (UPCité), Centre de Recherche en Cancérologie de Marseille (CRCM), Aix Marseille Université (AMU)-Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Guerineau, Nathalie C., Laboratoires d'excellence - Optimization of therapeutic monoclonal antibodies development Better antibodies, better developed AND better used - - MAbImprove2010 - ANR-10-LABX-0053 - LABX - VALID, Modulation de la synapse glutamatergique à l'aide de nanobodies - - nanoGluAct2015 - ANR-15-CE18-0020 - AAPG2015 - VALID, Développment d'une infrastructure française distribuée coordonnée - - France-BioImaging2010 - ANR-10-INBS-0004 - INBS - VALID, APPEL À PROJETS GÉNÉRIQUE 2018 - Dynamique structurale d'un RCPG dimérique en molécule unique - - DynaMuR22018 - ANR-18-CE11-0004 - AAPG2018 - VALID, Université de Paris - UFR Sciences du Vivant [Sciences] (UP - UFR SDV), and UFR Sciences du Vivant [Sciences] - Université Paris Cité (UFR SDV UPCité)
Subjects: Allosteric modulator, Protein Conformation, [SDV]Life Sciences [q-bio], Allosteric regulation, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, Receptors, Metabotropic Glutamate, Models, Biological, 03 medical and health sciences, 0302 clinical medicine, Humans, Receptor, agonist, [SDV.BC] Life Sciences [q-bio]/Cellular Biology, single-domain antibody, 030304 developmental biology, G protein-coupled receptor, 0303 health sciences, Multidisciplinary, Chemistry, Metabotropic glutamate receptor 4, Glutamate receptor, Glutamate binding, Single-Domain Antibodies, Biological Sciences, activation mechanism, 3. Good health, Cell biology, [SDV] Life Sciences [q-bio], Metabotropic receptor, Gene Expression Regulation, G protein–coupled receptor, Mutation, 030217 neurology & neurosurgery, Protein Binding
Abstract: International audience; There is growing interest in developing biologics due to their high target selectivity. The G protein-coupled homo- and heterodimeric metabotropic glutamate (mGlu) receptors regulate many synapses and are promising targets for the treatment of numerous brain diseases. Although subtype-selective allosteric small molecules have been reported, their effects on the recently discovered heterodimeric receptors are often not known. Here, we describe a nanobody that specifically and fully activates homodimeric human mGlu4 receptors. Molecular modeling and mutagenesis studies revealed that the nanobody acts by stabilizing the closed active state of the glutamate binding domain by interacting with both lobes. In contrast, this nanobody does not activate the heterodimeric mGlu2-4 but acts as a pure positive allosteric modulator. These data further reveal how an antibody can fully activate a class C receptor and bring further evidence that nanobodies represent an alternative way to specifically control mGlu receptor subtypes.
Published: 2021

35. Agonists and allosteric modulators promote signaling from different metabotropic glutamate receptor 5 conformations

Author: François Hoh, Julie Kniazeff, Juan Lorenzo Catena, Cyril Goudet, Jean-Philippe Pin, Xavier Gómez-Santacana, Anaëlle Dumazer, Jean-Louis Banères, Ludovic Berto, Fanny Malhaire, Amadeu Llebaria, Robert B. Quast, Alice E. Berizzi, Giuseppe Cannone, Kutti R. Vinothkumar, Chia-Ying Huang, Chady Nasrallah, Guillaume Lebon, Julie Briot, Joan Font-Ingles, Karine Rottier, Institut de Génomique Fonctionnelle (IGF), Université de Montpellier (UM)-Université Montpellier 1 (UM1)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Montpellier 2 - Sciences et Techniques (UM2)-Centre National de la Recherche Scientifique (CNRS), MRC Laboratory of Molecular Biology [Cambridge, UK] (LMB), University of Cambridge [UK] (CAM)-Medical Research Council, Paul Scherrer Institute (PSI), Centre de Biochimie Structurale [Montpellier] (CBS), Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut des Biomolécules Max Mousseron [Pôle Chimie Balard] (IBMM), Ecole Nationale Supérieure de Chimie de Montpellier (ENSCM)-Institut de Chimie du CNRS (INC)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Laboratory of Medicinal Chemistry, Institute for Advanced Chemistry of Catalonia (MCS (IQAC-CSIC)), Tata Institute for Fundamental Research (TIFR), Ministerio de Ciencia e Innovación (España), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Guerineau, Nathalie C., MRC, Lab Mol Biol, Cambridge, England, Partenaires INRAE, The Swiss Light Source (SLS) (SLS-PSI), Ecole Nationale Supérieure de Chimie de Montpellier (ENSCM)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Institut de Química Avançada de Catalunya (IQAC), Consejo Superior de Investigaciones Científicas [Spain] (CSIC), and National Centre for Biological Sciences [TIFR] (NCBS)
Subjects: Models, Molecular, Allosteric modulators, [SDV]Life Sciences [q-bio], G-protein-coupled receptors, Signal transduction, Crystallography, X-Ray, photochromic ligands, Excitatory Amino Acid Agonists, Receptor, Cryo-EM, 0303 health sciences, Metabotropic glutamate receptor 5, Chemistry, Protein Stability, 030302 biochemistry & molecular biology, metabotropic glutamate receptor 5, Glutamate receptor, 3. Good health, [SDV.BBM.BP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biophysics, [SDV] Life Sciences [q-bio], allosteric modulators, Glutamate, signal transduction, Protein Binding, Agonist, animal structures, medicine.drug_class, Receptor, Metabotropic Glutamate 5, Allosteric regulation, glutamate, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, General Biochemistry, Genetics and Molecular Biology, Article, 03 medical and health sciences, Structure-Activity Relationship, medicine, [CHIM.CRIS]Chemical Sciences/Cristallography, Humans, Protein Interaction Domains and Motifs, [CHIM.CRIS] Chemical Sciences/Cristallography, [SDV.BC] Life Sciences [q-bio]/Cellular Biology, 030304 developmental biology, G protein-coupled receptor, X-ray crystallography, Cryoelectron Microscopy, Protein Subunits, HEK293 Cells, Metabotropic glutamate receptor, Photochromic ligands, Biophysics, cryo-EM, Excitatory Amino Acid Antagonists
Abstract: Summary Metabotropic glutamate receptors (mGluRs) are dimeric G-protein-coupled receptors activated by the main excitatory neurotransmitter, L-glutamate. mGluR activation by agonists binding in the venus flytrap domain is regulated by positive (PAM) or negative (NAM) allosteric modulators binding to the 7-transmembrane domain (7TM). We report the cryo-electron microscopy structures of fully inactive and intermediate-active conformations of mGlu5 receptor bound to an antagonist and a NAM or an agonist and a PAM, respectively, as well as the crystal structure of the 7TM bound to a photoswitchable NAM. The agonist induces a large movement between the subunits, bringing the 7TMs together and stabilizing a 7TM conformation structurally similar to the inactive state. Using functional approaches, we demonstrate that the PAM stabilizes a 7TM active conformation independent of the conformational changes induced by agonists, representing an alternative mode of mGlu activation. These findings provide a structural basis for different mGluR activation modes., Graphical abstract, Highlights • Cryo-EM analysis of thermostabilized mGlu5 receptor bound to inhibitors or activators • X-ray structure of trans-Alloswitch-1 bound to thermostable mGlu5 7TMs • Photopharmacology provides insight into allosteric regulation of mGlu5 7TMs • Multiple conformations of mGlu5 receptor activate G protein, Nasrallah et al. present cryo-EM structures of thermostabilized mGlu5 dimer bound to inhibitors and activators as well as an X-ray structure of mGlu5 7TM-bound photoswitchable ligand alloswitch-1. The structural and functional analyses reveal different modes of mGLu5 receptor activation and provide a structural basis for mGlu receptor activation mechanism.
Published: 2021

36. Ligands and DNA in the allosteric control of retinoid receptors function

Author: Natacha Rochel, William Bourguet, Pierre Germain, Centre de Biochimie Structurale [Montpellier] (CBS), Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), and Rochel, Natacha
Subjects: retinoids, Receptors, Retinoic Acid, medicine.drug_class, [SDV]Life Sciences [q-bio], Allosteric regulation, Retinoic acid, retinoic acid receptor, Retinoid X receptor, Ligands, Biochemistry, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, medicine, Animals, Retinoid, Receptor, Molecular Biology, Transcription factor, 030304 developmental biology, 0303 health sciences, Promoter, DNA, allosteric regulation, Cell biology, [SDV] Life Sciences [q-bio], Retinoic acid receptor, Retinoid X Receptors, chemistry, transcription, 030217 neurology & neurosurgery
Abstract: Retinoids are a family of compounds that include both vitamin A (all-trans retinol) and its naturally occurring metabolites such as retinoic acids (e.g. all-trans retinoic acid) as well as synthetic analogs. They are critically involved in the regulation of a wide variety of essential biological processes, such as embryogenesis and organogenesis, apoptosis, reproduction, vision, and the growth and differentiation of normal and neoplastic cells in vertebrates. The ability of these small molecules to control the expression of several hundred genes through binding to nuclear ligand-dependent transcription factors accounts for most of their functions. Three retinoic acid receptor (RARα,β,γ) and three retinoid X receptor (RXRα,β,γ) subtypes form a variety of RXR–RAR heterodimers that have been shown to mediate the pleiotropic effects of retinoids through the recruitment of high-molecular weight co-regulatory complexes to response-element DNA sequences found in the promoter region of their target genes. Hence, heterodimeric retinoid receptors are multidomain entities that respond to various incoming signals, such as ligand and DNA binding, by allosteric structural alterations which are the basis of further signal propagation. Here, we provide an overview of the current state of knowledge with regard to the structural mechanisms by which retinoids and DNA response elements act as allosteric effectors that may combine to finely tune RXR–RAR heterodimers activity.
Published: 2021

37. The impact of space and time on the functional output of the nucleus

Author: Nollmann, Marcelo, Bennabi, Isma, Götz, Markus, Gregor, Thomas, Centre de Biochimie Structurale [Montpellier] (CBS), Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM), Physique des fonctions biologiques / Physics of Biological Functions, Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), Department of Physics, Princeton University (DPPU), Princeton University, Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), Nollmann, Marcelo, Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Ana Pombo, Martin Hetzer, Tom Misteli, and Gregor, Thomas
Subjects: [SDV] Life Sciences [q-bio], [SDV.BIBS] Life Sciences [q-bio]/Quantitative Methods [q-bio.QM], [SDV]Life Sciences [q-bio], [SDV.BDD] Life Sciences [q-bio]/Development Biology, [SDV.BC.BC] Life Sciences [q-bio]/Cellular Biology/Subcellular Processes [q-bio.SC], [SDV.BC.BC]Life Sciences [q-bio]/Cellular Biology/Subcellular Processes [q-bio.SC], [SDV.BBM.BC]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biochemistry [q-bio.BM], [SDV.BIBS]Life Sciences [q-bio]/Quantitative Methods [q-bio.QM], [SDV.BDD]Life Sciences [q-bio]/Development Biology, [SDV.BBM.BC] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biochemistry [q-bio.BM]
Abstract: Article également paru le 6 juillet 2021 dans Cold Spring Harbor Perspectives in Biology, DOI 10.1101/cshperspect.a040378; International audience; Over the past two decades, it has become clear that the multi-scale spatial and temporal organization of the genome has important implications for nuclear function. This chapter centers on insights gained from recent advances in light microscopy on our understanding of transcription. Particular focus is given to the genomic scales where most functional interactions occur, namely kb-Mb. We discuss the relevant spatial and temporal scales that shape nuclear order and their consequences on regulatory components and function. The emerging picture is that spatiotemporal constraints increase the complexity in transcriptional regulation. This brings new challenges to the fore, such as uncertainty about how information travels from factors through the genome and space to generate a functional output.
Published: 2021

38. A Novel Approach to the Facile Growth and Organization of Photothermal Prussian Blue Nanocrystals on Different Surfaces

Author: Yannick Guari, Luca Costa, Christophe Dorandeu, Gautier Félix, Pierre-Emmanuel Milhiet, Jean-Marie Devoisselle, Giang Ngo, Joël Chopineau, Joulia Larionova, Institut Charles Gerhardt Montpellier - Institut de Chimie Moléculaire et des Matériaux de Montpellier (ICGM ICMMM), Ecole Nationale Supérieure de Chimie de Montpellier (ENSCM)-Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM)-Université Montpellier 1 (UM1)-Université Montpellier 2 - Sciences et Techniques (UM2)-Institut de Chimie du CNRS (INC), Centre de Biochimie Structurale [Montpellier] (CBS), Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM), Félix, Gautier, Institut Charles Gerhardt Montpellier - Institut de Chimie Moléculaire et des Matériaux de Montpellier (ICGM), Ecole Nationale Supérieure de Chimie de Montpellier (ENSCM)-Institut de Chimie du CNRS (INC)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), and Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS)
Subjects: Materials science, Nanostructure, General Chemical Engineering, supported lipid bilayers, Nanoparticle, 02 engineering and technology, 010402 general chemistry, 01 natural sciences, Article, chemistry.chemical_compound, surface growth, Homogeneity (physics), nanostructures, General Materials Science, Laser power scaling, Lipid bilayer, QD1-999, Prussian blue, [CHIM.MATE] Chemical Sciences/Material chemistry, atomic force microscopy, [CHIM.MATE]Chemical Sciences/Material chemistry, gold surface, Photothermal therapy, 021001 nanoscience & nanotechnology, 0104 chemical sciences, Chemistry, Chemical engineering, chemistry, Nanocrystal, films, 0210 nano-technology
Abstract: We report here a novel “one-pot” approach for the controlled growth and organization of Prussian blue nanostructures on three different surfaces: pure Au0, cysteamine-functionalized Au0, and SiO2-supported lipid bilayers with different natures of lipids. We demonstrate that fine control over the size, morphology, and the degree and homogeneity of the surface coverage by Prussian Blue (PB) nanostructures may be achieved by manipulating different parameters, which are the precursor concentration, the nature of the functional groups or the nature of lipids on the surfaces. This allows the growth of isolated PB nanopyramids and nanocubes or the design of thin dense films over centimeter square surfaces. The formation of unusual Prussian blue nanopyramids is discussed. Finally, we demonstrate, by using experimental techniques and theoretical modeling, that PB nanoparticles deposited on the gold surface exhibit strong photothermal properties, permitting a rapid temperature increase up to 90 °C with a conversion of the laser power of almost 50% for power source heat.
Published: 2021

39. Arginine multivalency stabilizes protein/RNA condensates

Author: Matteo Paloni, Alessandro Barducci, Giovanni Bussi, Centre de Biochimie Structurale [Montpellier] (CBS), and Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM)
Subjects: Poly U, Arginine, Full‐Length Papers, Lysine, Stacking, RNA/protein interaction, 010402 general chemistry, Biochemistry, 01 natural sciences, Settore FIS/03 - Fisica della Materia, 03 medical and health sciences, Molecular dynamics, RNA-Protein Interaction, Polylysine, Molecular Biology, ComputingMilieux_MISCELLANEOUS, coacervates, 030304 developmental biology, chemistry.chemical_classification, 0303 health sciences, Oligonucleotide, Chemistry, Hydrogen bond, Biomolecule, 030302 biochemistry & molecular biology, RNA, liquid-liquid phase separation, molecular dynamics simulations, 0104 chemical sciences, [CHIM.THEO]Chemical Sciences/Theoretical and/or physical chemistry, Biophysics, Peptides
Abstract: Biomolecular condensates assembled through liquid-liquid phase separation (LLPS) of proteins and RNAs are currently recognized to play an important role in cellular organization. Their assembly depends on the formation of a network of transient, multivalent interactions between flexible scaffold biomolecules. Understanding how protein and RNA sequences determine these interactions and ultimately regulate the phase separation is an open key challenge. Recent in vitro studies have revealed that arginine and lysine residues, which are enriched in most cellular condensates, have markedly distinct propensities to drive the LLPS of protein/RNA mixtures. Here, we employ explicit-solvent atomistic Molecular Dynamics (MD) simulations to shed light on the microscopic origin of this difference by investigating mixtures of polyU oligonucleotides with either polyR/polyK peptides. In agreement with experiments, our simulations indicate that arginine has a higher affinity for polyU than lysine both in highly diluted conditions and in concentrated solutions with a biomolecular density comparable to cellular condensate. The analysis of intermolecular contacts suggests that this differential behavior is due to the propensity of arginine side chains to simultaneously form a higher number of specific interactions with oligonucleotides, including hydrogen bonds and stacking interactions. Our results provide a molecular description of how the multivalency of the guanidinium group enables the coordination of multiple RNA groups by a single arginine residue, thus ultimately stabilizing protein/RNA condensates.
Published: 2021

40. Comparative Assessment of NMR Probes for the Experimental Description of Protein Folding Pathways with High-Pressure NMR

Author: Yinshan Yang, Vincent Van Deuren, Christian Roumestand, Catherine Anne Royer, Philippe Barthe, Cécile Dubois, Karine de Guillen, Centre de Biochimie Structurale [Montpellier] (CBS), Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Rensselaer Polytechnic Institute (RPI), ANR-10-INBS-0005,FRISBI,Infrastructure Française pour la Biologie Structurale Intégrée(2010), BARTHE, Philippe, and Infrastructure Française pour la Biologie Structurale Intégrée - - FRISBI2010 - ANR-10-INBS-0005 - INBS - VALID
Subjects: Life Sciences & Biomedicine - Other Topics, DYNAMICS, 0301 basic medicine, [SDV.BBM.BS] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Structural Biology [q-bio.BM], STAPHYLOCOCCAL NUCLEASE, Stereochemistry, QH301-705.5, [SDV]Life Sciences [q-bio], Hydrostatic pressure, Sequence (biology), Biology, 010402 general chemistry, SEQUENCE, 01 natural sciences, General Biochemistry, Genetics and Molecular Biology, Article, 03 medical and health sciences, chemistry.chemical_compound, Amide, protein folding, Molecule, Biology (General), ENERGY LANDSCAPE, Science & Technology, SPECTROSCOPY, [SDV.BBM.BS]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Structural Biology [q-bio.BM], STABILITY, General Immunology and Microbiology, high hydrostatic pressure, NMR, 0104 chemical sciences, Folding (chemistry), 030104 developmental biology, STATES, chemistry, Yield (chemistry), thermodynamic stability, Chemical stability, Protein folding, General Agricultural and Biological Sciences, Life Sciences & Biomedicine
Abstract: Simple Summary During the last decade, high-pressure multidimensional NMR has emerged as a very powerful tool to describe the folding landscapes of proteins. This is (i) because pressure is a gentle perturbation, the effects of which originate from local properties of the folded state, contrary to chemical or thermal denaturation, and (ii) because multidimensional NMR intrinsically provides multiple probes strategically scattered on the three-dimensional structure of the protein, allowing a quasi-atomic resolution to describe the folding pathway. Residue-specific information obtained from these probes can be used to describe protein folding pathways through the calculation of NMR-derived fractional probabilities of contact at increasing pressure. Here, we used this strategy to evaluate and compare the results obtained from NH amide, CαHα, and CH3 groups when used as NMR probes to explore the folding pathway of the model protein ∆+PHS Staphylococcal Nuclease. Abstract Multidimensional NMR intrinsically provides multiple probes that can be used for deciphering the folding pathways of proteins: NH amide and CαHα groups are strategically located on the backbone of the protein, while CH3 groups, on the side-chain of methylated residues, are involved in important stabilizing interactions in the hydrophobic core. Combined with high hydrostatic pressure, these observables provide a powerful tool to explore the conformational landscapes of proteins. In the present study, we made a comparative assessment of the NH, CαHα, and CH3 groups for analyzing the unfolding pathway of ∆+PHS Staphylococcal Nuclease. These probes yield a similar description of the folding pathway, with virtually identical thermodynamic parameters for the unfolding reaction, despite some notable differences. Thus, if partial unfolding begins at identical pressure for these observables (especially in the case of backbone probes) and concerns similar regions of the molecule, the residues involved in contact losses are not necessarily the same. In addition, an unexpected slight shift toward higher pressure was observed in the sequence of the scenario of unfolding with CαHα when compared to amide groups.
Published: 2021

41. Mechanical Control of Cell Migration by the Metastasis Suppressor Tetraspanin CD82/KAI1

Author: Diala Kantar, Luca Costa, Fedor Berditchevski, Laurent Fernandez, Lucie Chauvin, Christopher Chevillard, Elena Odintsova, Laura Ordas, Patrice Dosset, Lisa Heron-Milhavet, Anthony Lozano, Alexia Calovoulos, Christine Benistant, Christine Doucet, Pierre-Emmanuel Milhiet, Centre de Biochimie Structurale [Montpellier] (CBS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Institut de Génétique Moléculaire de Montpellier (IGMM), Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Institut de biologie structurale (IBS - UMR 5075), Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Grenoble Alpes (UGA), Institut de Recherche en Cancérologie de Montpellier (IRCM - U1194 Inserm - UM), CRLCC Val d'Aurelle - Paul Lamarque-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Acides Nucléiques : Régulations Naturelle et Artificielle (ARNA), Université de Bordeaux (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Institut de Génétique et Développement de Rennes (IGDR), Université de Rennes (UR)-Centre National de la Recherche Scientifique (CNRS)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Institute of Cancer and Genomic Sciences, University of Birmingham, Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM), Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique )-Centre National de la Recherche Scientifique (CNRS)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES), and Milhiet, Pierre-Emmanuel
Subjects: cell migration, QH301-705.5, Cell, Caveolin 1, [SDV.BBM.BP] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biophysics, [SDV.CAN]Life Sciences [q-bio]/Cancer, Kangai-1 Protein, plasma membrane, Mechanotransduction, Cellular, Article, Cell Line, Focal adhesion, 03 medical and health sciences, 0302 clinical medicine, [SDV.CAN] Life Sciences [q-bio]/Cancer, Tetraspanin, Cell Movement, Caveolae, Cell Line, Tumor, Neoplasms, Stress Fibers, Caveolin, medicine, Cell Adhesion, Humans, Biology (General), Mechanotransduction, Neoplasm Metastasis, 030304 developmental biology, caveolins, mechanotransduction, 0303 health sciences, Chemistry, Cell Membrane, Membrane Proteins, Cell migration, General Medicine, focal adhesions, Cell biology, tetraspanins, [SDV.BBM.BP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biophysics, medicine.anatomical_structure, 030220 oncology & carcinogenesis, YAP, CD82, actin, Signal Transduction, Transcription Factors
Abstract: International audience; The plasma membrane is a key actor of cell migration. For instance, its tension controls persistent cell migration and cell surface caveolae integrity. Then, caveolae constituents such as caveolin-1 can initiate a mechanotransduction loop that involves actin- and focal adhesion-dependent control of the mechanosensor YAP to finely tune cell migration. Tetraspanin CD82 (also named KAI-1) is an integral membrane protein and a metastasis suppressor. Its expression is lost in many cancers including breast cancer. It is a strong inhibitor of cell migration by a little-known mechanism. We demonstrated here that CD82 controls persistent 2D migration of EGF-induced single cells, stress fibers and focal adhesion sizes and dynamics. Mechanistically, we found that CD82 regulates membrane tension, cell surface caveolae abundance and YAP nuclear translocation in a caveolin-1-dependent manner. Altogether, our data show that CD82 controls 2D cell migration using membrane-driven mechanics involving caveolin and the YAP pathway.
Published: 2021

42. The study of the determinants controlling Arpp19 phosphatase-inhibitory activity reveals an Arpp19/PP2A-B55 feedback loop

Author: Jean-Claude Labbé, Sylvain Roque, Francisca Mechali, Cindy Genoud, Suzanne Vigneron, Anna Castro, Thierry Lorca, Martin Cohen-Gonsaud, Gilles Labesse, Perle Robert, Perrine Goguet-Rubio, Phillipe Barthe, Centre de recherche en Biologie Cellulaire (CRBM), Université Montpellier 2 - Sciences et Techniques (UM2)-Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM)-Université Montpellier 1 (UM1), Centre de Biochimie Structurale [Montpellier] (CBS), Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM), Lorca, Thierry, Centre de recherche en Biologie cellulaire de Montpellier (CRBM), Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), and Université Montpellier 1 (UM1)-Université Montpellier 2 - Sciences et Techniques (UM2)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS)
Subjects: 0301 basic medicine, inorganic chemicals, Cell division, Xenopus, Science, [SDV]Life Sciences [q-bio], Phosphatase, Cyclin B, General Physics and Astronomy, Mitosis, macromolecular substances, Xenopus Proteins, environment and public health, General Biochemistry, Genetics and Molecular Biology, Article, Feedback, Dephosphorylation, 03 medical and health sciences, Xenopus laevis, 0302 clinical medicine, CDC2 Protein Kinase, Phosphoprotein Phosphatases, Animals, Protein Phosphatase 2, Phosphorylation, Cyclin-dependent kinase 1, Multidisciplinary, biology, Chemistry, Kinase, General Chemistry, Protein phosphatase 2, Phosphoproteins, 3. Good health, Cell biology, [SDV] Life Sciences [q-bio], Meiosis, enzymes and coenzymes (carbohydrates), 030104 developmental biology, biology.protein, bacteria, Female, Carboxylic Ester Hydrolases, 030217 neurology & neurosurgery
Abstract: Arpp19 is a potent PP2A-B55 inhibitor that regulates this phosphatase to ensure the stable phosphorylation of mitotic/meiotic substrates. At G2-M, Arpp19 is phosphorylated by the Greatwall kinase on S67. This phosphorylated Arpp19 form displays a high affinity to PP2A-B55 and a slow dephosphorylation rate, acting as a competitor of PP2A-B55 substrates. The molecular determinants conferring slow dephosphorylation kinetics to S67 are unknown. PKA also phosphorylates Arpp19. This phosphorylation performed on S109 is essential to maintain prophase I-arrest in Xenopus oocytes although the underlying signalling mechanism is elusive. Here, we characterize the molecular determinants conferring high affinity and slow dephosphorylation to S67 and controlling PP2A-B55 inhibitory activity of Arpp19. Moreover, we show that phospho-S109 restricts S67 phosphorylation by increasing its catalysis by PP2A-B55. Finally, we discover a double feed-back loop between these two phospho-sites essential to coordinate the temporal pattern of Arpp19-dependent PP2A-B55 inhibition and Cyclin B/Cdk1 activation during cell division., Progression of the cell division cycle requires feedback loops including those of phosphorylation and dephosphorylation; however the precise regulation of phosphorylation kinetics of Arpp19, an inhibitor of protein phosphatase 2A, is unclear. Here, the authors report that feedback between phosphorylation states of Ser67 and Ser109 of Arpp19 coordinates Arpp19-dependent inhibition of PP2A-B55 and Cyclin B activation during cell cycle progression.
Published: 2021

43. Pharmacological activation of PIEZO1 in human red blood cells prevents Plasmodium falciparum invasion

Author: Rachel Cerdan, Dominique Douguet, Laurence Berry, Hélène Guizouarn, Roberto Bernal, Jordy Le Guet, Rakhee Lohia, Manouk Abkarian, Eric Honoré, Kai Wengelnik, LPHI - Laboratory of Pathogen Host Interactions (LPHI), Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Institut de Biologie Valrose (IBV), Université Nice Sophia Antipolis (... - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Côte d'Azur (UCA)-Centre National de la Recherche Scientifique (CNRS), Universidad de Santiago de Chile [Santiago] (USACH), Centre de Biochimie Structurale [Montpellier] (CBS), Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut de pharmacologie moléculaire et cellulaire (IPMC), Centre National de la Recherche Scientifique (CNRS)-Université Nice Sophia Antipolis (... - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Université Côte d'Azur (UCA), Institut National de la Santé et de la Recherche Médicale (INSERM), Wengelnik, Kai, Université Nice Sophia Antipolis (1965 - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Côte d'Azur (UCA), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), and COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Centre National de la Recherche Scientifique (CNRS)-Université Côte d'Azur (UCA)
Subjects: 0303 health sciences, biology, Chemistry, Activator (genetics), PIEZO1, Plasmodium falciparum, Parasitemia, medicine.disease, biology.organism_classification, 3. Good health, Microbiology, 03 medical and health sciences, Red blood cell, 0302 clinical medicine, medicine.anatomical_structure, [SDV.MP]Life Sciences [q-bio]/Microbiology and Parasitology, parasitic diseases, medicine, Mechanosensitive channels, Receptor, [SDV.MP] Life Sciences [q-bio]/Microbiology and Parasitology, 030217 neurology & neurosurgery, Intracellular, 030304 developmental biology
Abstract: An inherited gain-of–function variant (E756 del) in the mechanosensitive cationic channel PIEZO1 was recently shown to confer a significant protection against severe malaria. Here, we demonstrate in vitro that human red blood cell (RBC) infection by Plasmodium falciparum is prevented by the pharmacological activation of PIEZO1. The PIEZO1 activator Yoda1 inhibits RBC invasion, without affecting parasite intraerythrocytic growth, division or egress. RBC dehydration, echinocytosis and intracellular Na+/K+ imbalance are unrelated to the mechanism of protection. Inhibition of invasion is maintained, even after a prolonged wash out of Yoda1. Similarly, the chemically unrelated activators Jedi1 and Jedi2 potently inhibit parasitemia, further indicating a PIEZO1-dependent mechanism. Notably, Yoda1 treatment significantly reduced RBC surface receptors of P. falciparum, and decreased merozoite attachment and subsequent RBC deformation. Altogether these data indicate that the pharmacological activation of Piezo1 in human RBCs inhibits malaria infection by impairing P. falciparum invasion.
Published: 2021

44. Resolving the activation mechanism of the D99N antiterminator LicT protein

Author: Jérôme Gracy, Hélène Déméné, Nathalie Declerck, Yinshan Yang, Centre de Biochimie Structurale [Montpellier] (CBS), Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Département Microbiologie et Chaîne Alimentaire - INRAE (MICA), Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), and Déméné, Hélène
Subjects: Models, Molecular, [SDV]Life Sciences [q-bio], Mutant, medicine.disease_cause, antitermination protein, 03 medical and health sciences, Bacterial Proteins, Protein Domains, Structural Biology, medicine, Point Mutation, Nuclear Magnetic Resonance, Biomolecular, ComputingMilieux_MISCELLANEOUS, 030304 developmental biology, 0303 health sciences, Mutation, Binding Sites, Effector, Chemistry, 030302 biochemistry & molecular biology, RNA, activation mechanism, NMR, Cell biology, [SDV] Life Sciences [q-bio], RNA, Bacterial, Antitermination, Phosphorylation, BglG, Protein Multimerization, Linker, Function (biology), signal transduction, Bacillus subtilis, Transcription Factors
Abstract: International audience; LicT is an antiterminator protein of the BglG family whose members are key players in the control of carbohydrate catabolism in bacteria. These antiterminators are generally composed of three modules, an N-terminal RNA-binding domain (CAT) followed by two homologous regulation modules (PRD1 and PRD2) that control the RNA binding activity of the effector domain via phosphorylation on conserved histidines. Although several structures of isolated domains of BglG-like proteins have been described, no structure containing CAT and at least one PRD simultaneously has yet been reported in an active state, precluding detailed understanding of signal transduction between modules. To fulfill this gap, we recently reported the complete NMR sequence assignment of a constitutively active mutant (D99N) CAT-PRD1*, which contains the effector domain and the first regulation domain of LicT. As a follow-up, we have determined and report here the 3D solution structure of this active, dimeric LicT construct (40 kDa). The structure reveals how the mutation constrains the PRD1 regulation domain into an active conformation which is transduced to CAT via a network of negatively charged residues belonging to PRD1 dimeric interface and to the linker region. In addition, our data support a model where BglG-type antitermination regulatory modules can only adopt a single conformation compatible with the active structure of the effector domain, regardless of whether activation is mediated by mutation on the first or second PRD. The linker between the effector and regulation modules appears to function as an adaptable hinge tuning the position of the functional modules.
Published: 2021

45. Molecular structure of the intact bacterial flagellar basal body

Author: Joseph J. E. Caesar, Ashley L. Nord, Justin C. Deme, Emily Furlong, Fabienne F. V. Chevance, Susan M. Lea, Kelly T. Hughes, Richard M. Berry, Steven Johnson, Sir William Dunn School of Pathology [Oxford], University of Oxford [Oxford], Center for Structural Biology (CCR, NCI), Central Oxford Structural Molecular Imaging Centre, University of Oxford, Centre de Biochimie Structurale [Montpellier] (CBS), Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM), University of Utah, Department of Biology, University of Oxford, Department of Physics, University of Oxford, Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), and Nord, Ashley
Subjects: Microbiology (medical), [SDV.BBM.BS] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Structural Biology [q-bio.BM], Immunology, Flagellum, Rotation, Applied Microbiology and Biotechnology, Microbiology, Article, law.invention, Cell wall, 03 medical and health sciences, Bacterial Proteins, Salmonella, law, Genetics, Inner membrane, ComputingMilieux_MISCELLANEOUS, 030304 developmental biology, 0303 health sciences, [SDV.BBM.BS]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Structural Biology [q-bio.BM], 030306 microbiology, Chemistry, Cryoelectron Microscopy, Cell Biology, Basal Bodies, Molecular machine, Membrane, Flagella, Bushing, Drive shaft, Biophysics, Bacterial outer membrane
Abstract: The bacterial flagellum is a macromolecular protein complex that enables motility in many species. Bacterial flagella self-assemble a strong, multicomponent drive shaft that couples rotation in the inner membrane to the micrometre-long flagellar filament that powers bacterial swimming in viscous fluids1–3. Here, we present structures of the intact Salmonella flagellar basal body4, encompassing the inner membrane rotor, drive shaft and outer-membrane bushing, solved using cryo-electron microscopy to resolutions of 2.2–3.7 A. The structures reveal molecular details of how 173 protein molecules of 13 different types assemble into a complex spanning two membranes and a cell wall. The helical drive shaft at one end is intricately interwoven with the rotor component with both the export gate complex and the proximal rod forming interactions with the MS-ring. At the other end, the drive shaft distal rod passes through the LP-ring bushing complex, which functions as a molecular bearing anchored in the outer membrane through interactions with the lipopolysaccharide. The in situ structure of a protein complex capping the drive shaft provides molecular insights into the assembly process of this molecular machine. The in situ cryo-electron microscopy structure of the intact Salmonella flagellar basal body—including the inner membrane rotor, drive shaft and outer membrane bushing complex—elucidates the mechanisms of assembly of this complex macromolecular structure that enables bacterial motility.
Published: 2021

46. Melanotransferrin is efficiently sorted on the surface of exosomes secreted by melanoma cells

Author: Gaëtan Bellot, Nesrine Aissaoui, Laurent Henry, Marie Morille, Michel Vidal, Anne Bonhoure, Pierre-Emmanuel Stoebner, Dynamique des interactions membranaires normales et pathologiques (DIMNP), Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM)-Université Montpellier 2 - Sciences et Techniques (UM2)-Université Montpellier 1 (UM1), Institut des Biomolécules Max Mousseron [Pôle Chimie Balard] (IBMM), Ecole Nationale Supérieure de Chimie de Montpellier (ENSCM)-Institut de Chimie du CNRS (INC)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Institut Charles Gerhardt Montpellier - Institut de Chimie Moléculaire et des Matériaux de Montpellier (ICGM ICMMM), Ecole Nationale Supérieure de Chimie de Montpellier (ENSCM)-Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM)-Université Montpellier 1 (UM1)-Université Montpellier 2 - Sciences et Techniques (UM2)-Institut de Chimie du CNRS (INC), Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Centre de Biochimie Structurale [Montpellier] (CBS), Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM), and Centre National de la Recherche Scientifique (CNRS)
Subjects: Cancer Research, Skin Neoplasms, Dermatology, Exosomes, Mice, Melanoma Biomarker, medicine, Animals, Humans, [CHIM]Chemical Sciences, Melanoma, neoplasms, ComputingMilieux_MISCELLANEOUS, Membrane Glycoproteins, CD63, biology, Chemistry, medicine.disease, Microvesicles, 3. Good health, Oncology, Cutaneous melanoma, Cancer cell, biology.protein, Cancer research, Melanotransferrin, Antibody
Abstract: Cutaneous melanoma is the most lethal type of skin cancer. Early detection is crucial to improve the outcome of melanoma patients. The identification of noninvasive prognostic biomarkers for the follow-up of melanoma patients is still in demand for clinical use. We show here that exosomal melanotransferrin fulfills the biomarker characteristics required to meet this demand. Melanotransferrin is typically overexpressed in melanoma cells compared to other cell types - including cancer cells - and is efficiently sorted and secreted with nanovesicles, or so-called exosomes, due to its membrane-anchoring by a glycosylphosphatidylinositol. Melanotransferrin is exposed on the surface of exosomes and is accessible for antibody recognition. An ELISA was set up to quantify melanotransferrin after immobilization of nanovesicles through the exosomal constituent tetraspanins CD63. Melanotransferrin was detected using a low number of exosomes purified from melanoma cell line cultures, and melanotransferrin detection was abolished by phosphatidylinositol-specific phospholipase C treatment. This exosomal melanotransferrin ELISA was able to discriminate an equal number of assayed exosomes purified from two different melanoma cell lines (A-375 vs. SK-MEL-28). Moreover, plasma samples from patients with melanoma and noncancer disease were assayed using this ELISA and elevated levels of exosomal melanotransferrin were seen in the plasma of patients with melanoma. We propose that exosomal melanotransferrin should be assessed as a potential melanoma biomarker.
Published: 2021

47. Développement de nouvelles approches de microscopie correlative AFM-Fluorescence pour l'analyse d'échantillons biologiques

Author: Saavedra V., Oscar, Centre de Biochimie Structurale [Montpellier] (CBS), Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Montpellier, and Pierre-Emmanuel Milhiet
Subjects: Rupture forces, Microscopies corrélatives, [SDV.SA]Life Sciences [q-bio]/Agricultural sciences, Correlative microscopies, Miet, Microscopie à force atomique, Membranes biologiques, Forces de rupture, Compression, Atomic Force Microscopy (AFM), Biological membranes, Metal Induced Energy Transfer (MIET)
Abstract: Biological membranes are flexibles barriers that ensure cell permeability, delineating the cell boundaries and the intracellular compartments to organelles within the cell. They are composed mainly by phospholipids and proteins. Those components are the main ones responsible for membrane remodeling. The latter process is highly dynamic and requires observation at high spatial and temporal resolution. This thesis work focused on two main challenges in the study of membranes: i) Softness of biological membranes and their mechanical properties. Membranes are very soft and fragile materials, and determine their real morphology is highly complicated due to their softness. We have studied the maximal force exerted by an AFM tip that supported lipid bilayers can withstand before rupture, as well as their Young’s modulus, both as a function of the tip size. ii) Chemical sensitivity and molecular recognition in microscopy. AFM can achieve the topography of the membrane. However, this technique cannot distinguish the molecule below the AFM tip. In order to overcome this barrier, we worked on developing a new fluorescence super-resolution technique combining AFM and confocal microscopies. First, we developed a correlated and synchronous confocal Fluorescence-lifetime imaging microscope (FLIM)-AFM setup. Finally, we developed a Metal Induced Energy Transfer (MIET)-AFM setup in order to measure molecular recognition, topography, and mechanical properties of biological samples simultaneously.; Les membranes biologiques sont des barrières flexibles qui assurent la perméabilité des cellules, délimitant les frontières cellulaires et les compartiments intracellulaires aux organites à l'intérieur de la cellule. Elles sont composées principalement de phospholipides et de protéines. Ces composants sont les principaux responsables du remodelage des membranes. Ce dernier processus est très dynamique et nécessite une observation à haute résolution latérale et temporelle. Ce travail de thèse s'est concentré sur deux défis principaux dans l'étude des membranes : i) Les propriétés mécaniques. Les membranes sont des matériaux très mous et fragiles, et déterminer leur morphologie réelle est très compliqué en raison de leur mollesse. Nous avons étudié la force maximale exercée par une pointe AFM que les bicouches lipidiques supportées peuvent supporter avant la rupture, ainsi que leur module d'Young, tous deux en fonction de la taille de la pointe. ii) Sensibilité chimique lors de l'imagerie des membranes. L'AFM permet d'obtenir la topographie de la membrane. Cependant, cette technique ne peut pas distinguer la molécule située sous la pointe de l'AFM. Afin de surmonter cet obstacle, nous avons travaillé à la mise au point d'une nouvelle technique de fluorescence à super-résolution combinant l'AFM et les microscopies confocales. Tout d'abord, nous avons mis au point un microscope confocal synchrone et corrélé d'imagerie de fluorescence à vie (FLIM)-AFM. Enfin, nous avons mis au point un dispositif de transfert d'énergie induit par les métaux (MIET)-AFM afin de mesurer simultanément la reconnaissance moléculaire, la topographie et les propriétés mécaniques des échantillons biologiques.
Published: 2021

48. Cryo–electron microscopy structure of the antidiuretic hormone arginine-vasopressin V2 receptor signaling complex

Author: Patrick Bron, Stefano Trapani, Hélène Orcel, Julien Bous, Nicolas Floquet, Remy Sounier, Cedric Leyrat, Aurelie Ancelin, Julie Saint-Paul, Sébastien Granier, Gérald Gaibelet, Joséphine Lai-Kee-Him, Hélène Déméné, Bernard Mouillac, Maxime Louet, Institut de Génomique Fonctionnelle (IGF), Université de Montpellier (UM)-Université Montpellier 1 (UM1)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Montpellier 2 - Sciences et Techniques (UM2)-Centre National de la Recherche Scientifique (CNRS), Centre de Biochimie Structurale [Montpellier] (CBS), Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut des Biomolécules Max Mousseron [Pôle Chimie Balard] (IBMM), Ecole Nationale Supérieure de Chimie de Montpellier (ENSCM)-Institut de Chimie du CNRS (INC)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), and Guerineau, Nathalie C.
Subjects: endocrine system, Gs alpha subunit, Cryo-electron microscopy, Protein subunit, [SDV]Life Sciences [q-bio], 01 natural sciences, 03 medical and health sciences, Structural Biology, Arginine vasopressin receptor 2, 0103 physical sciences, Receptor, Ternary complex, Research Articles, 030304 developmental biology, G protein-coupled receptor, 0303 health sciences, Multidisciplinary, 010304 chemical physics, Chemistry, urogenital system, SciAdv r-articles, 3. Good health, [SDV] Life Sciences [q-bio], Biophysics, hormones, hormone substitutes, and hormone antagonists, Antidiuretic, Research Article, Signal Transduction
Abstract: Structures of the AVP-V2R-Gs protein complex provide molecular insights into the function of this clinically relevant target., The antidiuretic hormone arginine-vasopressin (AVP) forms a signaling complex with the V2 receptor (V2R) and the Gs protein, promoting kidney water reabsorption. Molecular mechanisms underlying activation of this critical G protein–coupled receptor (GPCR) signaling system are still unknown. To fill this gap of knowledge, we report here the cryo–electron microscopy structure of the AVP-V2R-Gs complex. Single-particle analysis revealed the presence of three different states. The two best maps were combined with computational and nuclear magnetic resonance spectroscopy constraints to reconstruct two structures of the ternary complex. These structures differ in AVP and Gs binding modes. They reveal an original receptor-Gs interface in which the Gαs subunit penetrates deep into the active V2R. The structures help to explain how V2R R137H or R137L/C variants can lead to two severe genetic diseases. Our study provides important structural insights into the function of this clinically relevant GPCR signaling complex.
Published: 2021

49. Mammalian Mechanoelectrical Transduction: Structure and Function of Force-Gated Ion Channels

Author: Dominique Douguet, Eric Honoré, Centre de Biochimie Structurale [Montpellier] (CBS), Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut de pharmacologie moléculaire et cellulaire (IPMC), Université Nice Sophia Antipolis (... - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Centre National de la Recherche Scientifique (CNRS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Université Nice Sophia Antipolis (1965 - 2019) (UNS), and Honoré, Eric
Subjects: 0303 health sciences, [SDV]Life Sciences [q-bio], PIEZO1, Mechanoelectrical transduction, Depolarization, [SDV.BC.BC]Life Sciences [q-bio]/Cellular Biology/Subcellular Processes [q-bio.SC], Gating, Biology, General Biochemistry, Genetics and Molecular Biology, Autonomic regulation, Structure and function, [SDV] Life Sciences [q-bio], 03 medical and health sciences, 0302 clinical medicine, [SDV.BC.BC] Life Sciences [q-bio]/Cellular Biology/Subcellular Processes [q-bio.SC], Mechanosensitive channels, Neuroscience, ComputingMilieux_MISCELLANEOUS, 030217 neurology & neurosurgery, Ion channel, 030304 developmental biology
Abstract: The conversion of force into an electrical cellular signal is mediated by the opening of different types of mechanosensitive ion channels (MSCs), including TREK/TRAAK K2P channels, Piezo1/2, TMEM63/OSCA, and TMC1/2. Mechanoelectrical transduction plays a key role in hearing, balance, touch, and proprioception and is also implicated in the autonomic regulation of blood pressure and breathing. Thus, dysfunction of MSCs is associated with a variety of inherited and acquired disease states. Significant progress has recently been made in identifying these channels, solving their structure, and understanding the gating of both hyperpolarizing and depolarizing MSCs. Besides prototypical activation by membrane tension, additional gating mechanisms involving channel curvature and/or tethered elements are at play.
Published: 2019

50. Insights into the activation mechanism of human estrogen-related receptor γ by environmental endocrine disruptors

Author: Erwan Thouennon, Vanessa Delfosse, Rémy Bailly, Pauline Blanc, Abdelhay Boulahtouf, Marina Grimaldi, Alessandro Barducci, William Bourguet, Patrick Balaguer, Institut de Recherche en Cancérologie de Montpellier (IRCM - U1194 Inserm - UM), CRLCC Val d'Aurelle - Paul Lamarque-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Centre de Biochimie Structurale [Montpellier] (CBS), and Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM)
Subjects: Transcriptional Activation, Estrogen-related receptor γ, Molecular Dynamics Simulation, Crystallography, X-Ray, Ligands, 03 medical and health sciences, Cellular and Molecular Neuroscience, 0302 clinical medicine, Phenols, Cell Line, Tumor, Humans, Benzhydryl Compounds, [SDV.BBM.BC]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biochemistry [q-bio.BM], Endocrine disruptors, Molecular Biology, 030304 developmental biology, Pharmacology, 0303 health sciences, Binding Sites, [SDV.BBM.BS]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Structural Biology [q-bio.BM], Xenoestrogens, [SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, Cell Biology, Recombinant Proteins, Protein Structure, Tertiary, [SDV.BBM.BP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biophysics, Receptors, Estrogen, Thermodynamics, Molecular Medicine, Protein–ligand interaction, 030217 neurology & neurosurgery, Protein Binding
Abstract: International audience; The estrogen-related receptor γ (ERRγ, NR3B3) is a constitutively active nuclear receptor which has been proposed to act as a mediator of the low-dose effects of a number of environmental endocrine-disrupting chemicals (EDCs) such as the xenoestrogen bisphenol-A (BPA). To better characterize the ability of exogenous compounds to bind and activate ERRγ, we used a combination of cell-based, biochemical, structural and computational approaches. A purposely created stable cell line allowed for the determination of the EC50s for over 30 environmental ERRγ ligands, including previously unknown ones. Interestingly, affinity constants (Kds) of the most potent compounds measured by isothermal titration calorimetry were in the 50–500 nM range, in agreement with their receptor activation potencies. Crystallographic analysis of the interaction between the ERRγ ligand-binding domain (LBD) and compounds of the bisphenol, alkylphenol and naphthol families revealed a partially shared binding mode and minimal alterations of the receptor conformation upon ligand binding. Further biophysical characterizations coupled to molecular dynamics simulations suggested a mechanism through which ERRγ ligands would exhibit their agonistic properties by preserving the transcriptionally active form of the receptor while rigidifying some loop regions with associated functions. This unique mechanism contrasts with the classical one involving a ligand-induced repositioning and stabilization of the C-terminal activation helix H12.
Published: 2019

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