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5 results on '"MESH: Carrier Proteins/genetics"'

1. EHD2 is a mechanotransducer connecting caveolae dynamics with gene transcription

Author

Darius Vasco Köster, Cédric M. Blouin, Paolo Pierobon, Vassili Soumelis, Satish Kailasam Mani, Christine Viaris de Lesegno, Ludger Johannes, Alexandre Grassart, Valérie Chambon, Wei-Wei Shen, Stéphanie Torrino, Catherine Coirault, Cesar Augusto Valades-Cruz, Stéphane Vassilopoulos, Pierre Bost, Christophe Lamaze, Chimie biologique des membranes et ciblage thérapeutique (CBMCT - UMR 3666 / U1143), Centre National de la Recherche Scientifique (CNRS)-Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Chimie du CNRS (INC), Immunité et cancer (U932), Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Pathogénie microbienne moléculaire, Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Pasteur [Paris], Cell and Developmental Biology [Coventry, UK], Division of Biomedical Sciences [Coventry, UK], Warwick Medical School, University of Warwick [Coventry]-University of Warwick [Coventry]-Warwick Medical School, University of Warwick [Coventry]-University of Warwick [Coventry], Trafic endocytique et ciblage intracellulaire (CBMCT - UMR 3666 / U1143), Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut de Myologie, Centre National de la Recherche Scientifique (CNRS)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Association française contre les myopathies (AFM-Téléthon)-Sorbonne Université (SU), The AIC is jointly supported by the Gordon and Betty Moore Foundation and Howard Hughes Medical Institute. The electron microscope facility was supported by the ANR through 'Investments for the Future' program (France-BioImaging, ANR-10-INSB-04). This work was supported by institutional grants from the Institut Curie, Institut National de la Santé et de la Recherche Médicale, and Centre National de la Recherche Scientifique, and by specific grants from ANR (MECANOCAV, ANR-12-BSV2-0011, DECAV-RECAV, ANR-14-CE09-0008-03, and MOTICAV, ANR-17-CE-0013), Institut National du Cancer (INCa PLBIO12-203), Fondation de France, Marie Curie Actions—Networks for Initial Training (H2020-MSCA-ITN-2014), Association Française contre les Myopathies (15717 and 16754), and Program labellisé, Fondation ARC pour la Recherche sur le Cancer (PGA1 RF20170205456) to C. Lamaze, ANR (ANR-14-CE14-0002-02), Human Frontier Science Program (RGP0029-2014), and European Research Council (advanced grant 340485) to L. Johannes, ANR young researcher grant (EndoMechano ANR-14-CE12-0001-01) to S. Vassilopoulos. A. Grassart is supported by a Pasteur-Roux Fellowship. P. Pierobon is supported by grants from ANR (ANR-10-JCJC-1504-Immuphy) and PIC (Programme Incitatif et Collaboratif) Curie, 'Cell polarity, division, growth and cancer.' S. Torrino and W.-W. Shen were supported by a postdoctoral fellowship from Fondation ARC pour la Recherche sur le Cancer and Fondation de France, respectively. D. Köster and W.-W. Shen were supported by the Labex CelTisPhyBio Grants Program. The Johannes and Lamaze teams, the PICT-IBiSA/Nikon Imaging Centre at Institut Curie-Centre National de la Recherche Scientifique, and the France-BioImaging infrastructure are members of Labex CelTisPhyBio (ANR, ANR-10-LBX-0038) and of Initiatives d’Excellence (IDEX) PSL (ANR, ANR-10-IDEX-0001-02 PSL)., The facilities as well as scientific and technical assistance from the PICT-IBiSA/Nikon Imaging Centre staff at Institut Curie-Centre National de la Recherche Scientifique and the France-BioImaging infrastructure (Agence Nationale de la Recherche [ANR], ANR-10-INSB-04) are acknowledged. LLSM was performed at the Advanced Imaging Center (AIC) at Howard Hughes Medical Institute Janelia Research Campus., Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Curie [Paris], Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Association française contre les myopathies (AFM-Téléthon)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Institut Curie [Paris]-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 Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Paris Descartes - Paris 5 (UPD5)-Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Centre de recherche en Myologie – U974 SU-INSERM, Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Institut Curie-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Compartimentation et dynamique cellulaires (CDC), Centre National de la Recherche Scientifique (CNRS)-Institut Curie-Université Pierre et Marie Curie - Paris 6 (UPMC), Biologie du Développement et Reproduction (BDR), Institut National de la Recherche Agronomique (INRA), Centre de Bioinformatique, Biostatistique et Biologie Intégrative (C3BI), Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), Cell and Developmental Biology [Coventry, UK] (Warwick Medical School Biomedical Sciences), University of Warwick [Coventry], Laboratoire Trafic, Signalisation et Ciblage Intracellulaires, Institut Curie, Physico-Chimie-Curie (PCC), Centre de recherche en myologie, Université Pierre et Marie Curie - Paris 6 (UPMC)-Association française contre les myopathies (AFM-Téléthon)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Association française contre les myopathies (AFM-Téléthon)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), and Coirault, Catherine

Subjects
0301 basic medicine, Cell signaling, Transcription, Genetic, MESH: Mechanotransduction, Cellular, ATPase, [SDV]Life Sciences [q-bio], [SDV.BC]Life Sciences [q-bio]/Cellular Biology, Caveolae, Mechanotransduction, Cellular, MESH: Stress, Mechanical, Cell membrane, 03 medical and health sciences, Transcription (biology), MESH: Carrier Proteins/genetics, MESH: Carrier Proteins/metabolism, Report, medicine, Humans, Mechanotransduction, [SDV.BC] Life Sciences [q-bio]/Cellular Biology, Research Articles, MESH: Transcription, Genetic, Cancer, Regulation of gene expression, Trafficking, MESH: Humans, biology, MESH: Caveolae/metabolism, Cell Biology, QP, 3. Good health, Cell biology, [SDV] Life Sciences [q-bio], Cell nucleus, 030104 developmental biology, medicine.anatomical_structure, MESH: HeLa Cells, biology.protein, Stress, Mechanical, Carrier Proteins, Nucleus, HeLa Cells
Abstract

Caveolae are dynamic mechanosensors. Torrino et al. show that EHD2 plays a crucial role in the adaptation to mechanical perturbations by maintaining the caveolae reservoir at the plasma membrane after changes in membrane tension and connecting caveolae mechanosensing at the plasma membrane with the regulation of gene transcription., Caveolae are small invaginated pits that function as dynamic mechanosensors to buffer tension variations at the plasma membrane. Here we show that under mechanical stress, the EHD2 ATPase is rapidly released from caveolae, SUMOylated, and translocated to the nucleus, where it regulates the transcription of several genes including those coding for caveolae constituents. We also found that EHD2 is required to maintain the caveolae reservoir at the plasma membrane during the variations of membrane tension induced by mechanical stress. Metal-replica electron microscopy of breast cancer cells lacking EHD2 revealed a complete absence of caveolae and a lack of gene regulation under mechanical stress. Expressing EHD2 was sufficient to restore both functions in these cells. Our findings therefore define EHD2 as a central player in mechanotransduction connecting the disassembly of the caveolae reservoir with the regulation of gene transcription under mechanical stress.

Published
2018

2. rs11886868 and rs4671393 of BCL11A associated with HbF level variation and modulate clinical events among sickle cell anemia patients

Author

Imen Moumni, Leila Chaouch, Imen Boudrigua, Dorra Chaouachi, Miniar Kalai, Houyem Ouragini, Raouf Hafsia, Salem Abbes, Imen Darragi, Laboratoire d'hématologie moléculaire et cellulaire (LR11IPT07), Institut Pasteur de Tunis, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP), Université de Tunis El Manar (UTM), and LR11IPT07

Subjects
0301 basic medicine, Male, [SDV]Life Sciences [q-bio], BCL11A gene, MESH: Genotype, 0302 clinical medicine, Gene Frequency, hemic and lymphatic diseases, Genotype, MESH: Anemia, Sickle Cell/blood, Fetal Hemoglobin, education.field_of_study, MESH: Anemia, Sickle Cell/genetics, MESH: Polymorphism, Single Nucleotide, Nuclear Proteins, [SDV.MHEP.HEM]Life Sciences [q-bio]/Human health and pathology/Hematology, Hematology, Phenotype, Sickle cell anemia, 3. Good health, 030220 oncology & carcinogenesis, Female, Adult, congenital, hereditary, and neonatal diseases and abnormalities, Population, MESH: Nuclear Proteins/genetics, MESH: Fetal Hemoglobin/genetics, Anemia, Sickle Cell, Biology, Polymorphism, Single Nucleotide, 03 medical and health sciences, MESH: Carrier Proteins/genetics, Fetal hemoglobin, medicine, MESH: Fetal Hemoglobin/metabolism, MESH: Gene Frequency, Humans, education, Allele frequency, Genotyping, Gene, Retrospective Studies, MESH: Humans, HbF, MESH: Adult, MESH: Retrospective Studies, medicine.disease, MESH: Male, Repressor Proteins, 030104 developmental biology, Immunology, Carrier Proteins, MESH: Female
Abstract

International audience; Aims: Fetal hemoglobin (HbF) modulates the phenotype of sickle cell anemia (SCA) by inhibiting deoxy sickle hemoglobin (HbS) polymerization. HbF genes are genetically regulated, and the level of HbF and its distribution among sickle erythrocytes is highly variable. Herein, we aimed to determine whether two functional polymorphisms of BCL11A are implicated in the variation of HbF and clinical events in SCA Tunisian patients. Material and methods: The studied population consisted of 148 SCA patients with SS phenotype. The group of patients was divided into two subgroups according to the threshold point of %HbF which is 15%. Genotyping of rs11886868 and rs4671393 was performed using PCR/Sequencing. To test for trait association with the candidate SNPs, genotype and allele frequencies between `group who had %HbF < 15' and `group who had %HbF > 15' (controls) were compared using Pearson's chi-square test (compare 2, version 1.02). The association of each genotype and the combined genotype with complications was performed by logistic regression test. Results: Our findings showed that the majority of patients carried genotype CT of rs11886868 and genotypes AG and GG of rs4671393 present HbF level < 15%. RR = 0.08, RR = 0.176, and RR = 0.189, respectively. The results showed a significant association between the alleles T of rs11886868 and G of rs4671393 and %HbF < 15% with P = 0.016; RR = 0.39 and P = 8.9 x 10(-3): RR = 0.567, respectively. Interestingly, the C allele of the rs11886868 and the A allele of the rs46713939 were associated with an ameliorated phenotype in patient's SCA. The combination of the genotypes GG and CT explains more phenotypic variance than the sum of the two BCL11A SNPs taken individually.

Published
2016

3. Role of the Iron Axial Ligands of Heme Carrier HasA in Heme Uptake and Release

Author

Kenton R. Rodgers, Célia Caillet-Saguy, Muriel Delepierre, Anne Lecroisey, Mario Piccioli, Paola Turano, Gudrun S. Lukat-Rodgers, Nicolas Wolff, Nadia Izadi-Pruneyre, Résonance Magnétique Nucléaire des Biomolécules, Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), CERM and Deparment of Chemistry, Università degli Studi di Firenze = University of Florence (UniFI), North Dakota State University (NDSU), This work was supported, in whole or in part, by National Institutes of Health Grants GM094039 (to G. S. L. R.) and AI072719 (to K. R. R.)., We thank B. Guigliarelli for EPR data. Bio-NMR Project (Contract 261686) is acknowledged for providing access to NMR and NMRD instrumentations available at Center of Nuclear Magnetic Resonance., Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), and Università degli Studi di Firenze = University of Florence [Firenze] (UNIFI)

Subjects
Models, Molecular, Protein Folding, Protein Conformation, MESH: Heme/metabolism, Ligands, Spectrum Analysis, Raman, 01 natural sciences, Biochemistry, MESH: Bacterial Proteins/metabolism, chemistry.chemical_compound, Protein structure, MESH: Nuclear Magnetic Resonance, Biomolecular, MESH: Ligands, Metalloprotein, Heme, Serratia marcescens, Spectroscopy, chemistry.chemical_classification, 0303 health sciences, biology, digestive, oral, and skin physiology, MESH: Serratia marcescens/metabolism, MESH: Mutagenesis, Site-Directed, Protein Structure and Folding, Additions and Corrections, Protein folding, Heme Iron Spin State, MESH: Models, Molecular, MESH: Bacterial Proteins/chemistry, Hemophore HasA, MESH: Membrane Proteins/chemistry, MESH: Carrier Proteins/chemistry, Stereochemistry, Iron, MESH: Protein Folding, MESH: Bacterial Proteins/genetics, 010402 general chemistry, Cofactor, MESH: Membrane Proteins/genetics, 03 medical and health sciences, Bacterial Proteins, MESH: Carrier Proteins/genetics, MESH: Carrier Proteins/metabolism, Metalloproteins, MESH: Membrane Proteins/metabolism, Molecule, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, Nuclear Magnetic Resonance, Biomolecular, Molecular Biology, 030304 developmental biology, MESH: Spectrum Analysis, Raman, MESH: Iron/metabolism, 010405 organic chemistry, Ligand, Electron Spin Resonance Spectroscopy, Membrane Proteins, Cell Biology, Porphyrin, 0104 chemical sciences, Iron Acquisition, chemistry, Mutagenesis, Site-Directed, biology.protein, MESH: Electron Spin Resonance Spectroscopy, Carrier Proteins
Abstract

Erratum in : J Biol Chem. 2013 Jan 25;288(4):2190.; International audience; The hemophore protein HasA from Serratia marcescens cycles between two states as follows: the heme-bound holoprotein, which functions as a carrier of the metal cofactor toward the membrane receptor HasR, and the heme-free apoprotein fishing for new porphyrin to be taken up after the heme has been delivered to HasR. Holo- and apo-forms differ for the conformation of the two loops L1 and L2, which provide the axial ligands of the iron through His(32) and Tyr(75), respectively. In the apo-form, loop L1 protrudes toward the solvent far away from loop L2; in the holoprotein, closing of the loops on the heme occurs upon establishment of the two axial coordination bonds. We have established that the two variants obtained via single point mutations of either axial ligand (namely H32A and Y75A) are both in the closed conformation. The presence of the heme and one out of two axial ligands is sufficient to establish a link between L1 and L2, thanks to the presence of coordinating solvent molecules. The latter are stabilized in the iron coordination environment by H-bond interactions with surrounding protein residues. The presence of such a water molecule in both variants is revealed here through a set of different spectroscopic techniques. Previous studies had shown that heme release and uptake processes occur via intermediate states characterized by a Tyr(75)-iron-bound form with open conformation of loop L1. Here, we demonstrate that these states do not naturally occur in the free protein but can only be driven by the interaction with the partner proteins.

Published
2012

4. TRIM5 is an innate immune sensor for the retrovirus capsid lattice

Author

Christian Reinhard, Federico Santoni, Stéphane Hausmann, Matthew J Albert, Jessica Guerra, Aurélie Bisiaux, Caterina Strambio-De-Castillia, Thomas Pertel, Massimo Pizzato, Walther Mothes, Pradeep D. Uchil, Jeremy Luban, Josefina Lascano, Markus G. Grütter, Sara Züger, Laurence Chatel, Damien Morger, Département de Microbiologie et Médecine moléculaire, Université de Genève (UNIGE), Department of Biochemistry [Zurich], Universität Zürich [Zürich] = University of Zurich (UZH), Section of Microbial Pathogenesis, Yale University School of Medicine, Novimmune SA, Immunobiologie des Cellules Dendritiques, Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), This work was supported by NIH grant RO1AI59159 to J.L., NIH grant R21AI087467 to W.M., Swiss National Science Foundation grant 3100A0-128655 to J.L. and 3100A0-122342 to M.G., Université de Genève = University of Geneva (UNIGE), Yale School of Medicine [New Haven, Connecticut] (YSM), Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM), University of Zurich, and Luban, J

Subjects
Lipopolysaccharides, viruses, Ubiquitin-conjugating enzyme, Antiviral Restriction Factors, Tripartite Motif Proteins, Retrovirus, MESH: Ubiquitin-Protein Ligases/metabolism, Capsid/chemistry/immunology, MESH: Transcription Factors/metabolism, MESH: Capsid/immunology, ddc:616, 0303 health sciences, Multidisciplinary, biology, 030302 biochemistry & molecular biology, Pattern recognition receptor, NF-kappa B, Lipopolysaccharides/immunology/pharmacology, Ubiquitin-Protein Ligases/genetics/immunology/metabolism, MAP Kinase Kinase Kinases, MESH: HIV-1/chemistry, 3. Good health, Ubiquitin ligase, Retroviridae/chemistry/immunology, Capsid, MESH: Ubiquitin/metabolism, Receptors, Pattern Recognition, MESH: HEK293 Cells, MESH: HumansImmunity, Innate/immunology, MESH: Carrier Proteins/metabolism, [SDV.IMM]Life Sciences [q-bio]/Immunology, MESH: NF-kappa B/metabolism, Protein Binding, Signal Transduction, MESH: Ubiquitin-Protein Ligases/genetics, MESH: Receptors, Pattern Recognition/metabolism, MESH: Enzyme Activation, MESH: Ubiquitin-Protein Ligases/immunology, Ubiquitin-Protein Ligases, MESH: Lipopolysaccharides/pharmacology, Carrier Proteins/genetics/immunology/metabolism, Signal Transduction/drug effects/immunology, TRIM22, MESH: Lipopolysaccharides/immunology, Cell Line, MESH: Capsid/chemistry, 03 medical and health sciences, MESH: Receptors, Pattern Recognition/immunology, MESH: Carrier Proteins/genetics, MESH: Signal Transduction/drug effects, Immunity, Innate/immunology, Capsid/*chemistry/*immunology, Carrier Proteins/genetics/*immunology/*metabolism, Enzyme Activation, HEK293 Cells, HIV-1/chemistry/immunology, Humans, Immunity, Innate/*immunology, MAP Kinase Kinase Kinases/metabolism, NF-kappa B/metabolism, Receptors, Pattern Recognition/immunology/metabolism, Retroviridae/chemistry/*immunology, Transcription Factor AP-1/metabolism, Transcription Factors/metabolism, Ubiquitin/metabolism, Ubiquitin-Conjugating Enzymes/metabolism, 10019 Department of Biochemistry, MESH: Protein Binding, Avidity, 030304 developmental biology, 1000 Multidisciplinary, MESH: HIV-1/immunology, Innate immune system, MESH: Carrier Proteins/immunology, Ubiquitin, MESH: Signal Transduction/immunology, biology.organism_classification, Virology, Immunity, Innate, MESH: Ubiquitin-Conjugating Enzymes/metabolism, MESH: Cell Line, Transcription Factor AP-1, Retroviridae, Ubiquitin-Conjugating Enzymes, biology.protein, HIV-1, 570 Life sciences, MESH: Retroviridae/immunology, MESH: Retroviridae/chemistry, MESH: Transcription Factor AP-1/metabolism, Carrier Proteins, MESH: MAP Kinase Kinase Kinases/metabolism, Transcription Factors
Abstract

International audience; TRIM5 is a RING domain-E3 ubiquitin ligase that restricts infection by human immunodeficiency virus (HIV)-1 and other retroviruses immediately following virus invasion of the target cell cytoplasm. Antiviral potency correlates with TRIM5 avidity for the retrovirion capsid lattice and several reports indicate that TRIM5 has a role in signal transduction, but the precise mechanism of restriction is unknown. Here we demonstrate that TRIM5 promotes innate immune signalling and that this activity is amplified by retroviral infection and interaction with the capsid lattice. Acting with the heterodimeric, ubiquitin-conjugating enzyme UBC13-UEV1A (also known as UBE2N-UBE2V1), TRIM5 catalyses the synthesis of unattached K63-linked ubiquitin chains that activate the TAK1 (also known as MAP3K7) kinase complex and stimulate AP-1 and NFκB signalling. Interaction with the HIV-1 capsid lattice greatly enhances the UBC13-UEV1A-dependent E3 activity of TRIM5 and challenge with retroviruses induces the transcription of AP-1 and NF-κB-dependent factors with a magnitude that tracks with TRIM5 avidity for the invading capsid. Finally, TAK1 and UBC13-UEV1A contribute to capsid-specific restriction by TRIM5. Thus, the retroviral restriction factor TRIM5 has two additional activities that are linked to restriction: it constitutively promotes innate immune signalling and it acts as a pattern recognition receptor specific for the retrovirus capsid lattice.

Published
2011

5. Rabenosyn-5, a Novel Rab5 Effector, Is Complexed with Hvps45 and Recruited to Endosomes through a Fyve Finger Domain

Author

Marino Zerial, Bernard Hoflack, Marta Miaczynska, Sandrine Uttenweiler-Joseph, Erik Nielsen, Frédérique Dewitte, Savvas Christoforidis, Matthias Wilm, Max Planck Institute of Molecular Cell Biology and Genetics (MPI-CBG), Max-Planck-Gesellschaft, European Molecular Biology Laboratory [Heidelberg] (EMBL), Institut de biologie de Lille - UMS 3702 (IBL), Université de Lille-Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Centre National de la Recherche Scientifique (CNRS), E. Nielsen, S. Christofordis, and M. Miaczynska were recipients of European Molecular Biology Organization (EMBO) Long-term, Max-Planck, and Human Frontier Science Program Fellowships, respectively. This work was supported by the Max Planck Gesellschaft and by grants from the Human Frontier Science Program (RG-432/96), European Union-Training and Mobility of Researchers (EU TMR) (ERB-CT96-0020), and Biomed (BMH4-97-2410) (M. Zerial)., We are grateful to Drs. A. Klip, R. Piper, H. Stenmark, and R. Scheller for providing antibodies and plasmids. We would also like to thank A. Giner for technical assistance. Special thanks to Dr. H. McBride and S. De Renzis for valuable discussions and critical reading of the manuscript., Danish Road Institute, University of Ioannina, Laboratory of Cell Biology, International Institute of Molecular and Cell Biology, Unité de Glycobiologie Structurale et Fonctionnelle - UMR 8576 (UGSF), Université de Lille-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Recherche Agronomique (INRA), Cell Biology Programme, European Molecular Biology Laboratory, Institut de biologie de Lille - IBL (IBLI), Université de Lille, Sciences et Technologies-Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Université de Lille, Droit et Santé-Centre National de la Recherche Scientifique (CNRS), Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Université de Lille-Centre National de la Recherche Scientifique (CNRS), Unité de Glycobiologie Structurale et Fonctionnelle UMR 8576 (UGSF), Université de Lille-Institut National de la Recherche Agronomique (INRA)-Centre National de la Recherche Scientifique (CNRS), Université de Lille-Centre National de la Recherche Scientifique (CNRS), and Institut National de la Recherche Agronomique (INRA)-Université de Lille-Centre National de la Recherche Scientifique (CNRS)

Subjects
Munc18 Proteins, MESH: Sequence Homology, Amino Acid, Endocytic cycle, Vesicular Transport Proteins, Fluorescent Antibody Technique, MESH: Amino Acid Sequence, Nerve Tissue Proteins/chemistry, Membrane Fusion, MESH: Amino Acid Motifs, MESH: Protein Structure, Tertiary, 0302 clinical medicine, MESH: Qa-SNARE Proteins, MESH: Fluorescent Antibody Technique, ComputingMilieux_MISCELLANEOUS, 0303 health sciences, Effector, Cell biology, MESH: Endosomes/chemistry, Membrane Microdomains/chemistry/metabolism, Phosphatidylinositol 3-Kinases/metabolism, MESH: Protein Transport, rab5 GTP-Binding Proteins/*metabolism, MESH: Membrane Proteins/chemistry, Molecular Sequence Data, MESH: Sequence Alignment, MESH: Carrier Proteins/chemistry, Endosomes, Transfection, MESH: Membrane Fusion, EEA1, 03 medical and health sciences, MESH: Carrier Proteins/genetics, Humans, MESH: Protein Binding, MESH: Cloning, Molecular, Amino Acid Sequence, MESH: Humans, MESH: Molecular Sequence Data, Cathepsin D/metabolism, Rabenosyn-5, Protein Structure, Tertiary, MESH: Cell Line, FYVE domain, MESH: Phosphatidylinositol 3-Kinases/metabolism, Carrier Proteins, 030217 neurology & neurosurgery, HeLa Cells, MESH: Cathepsin D/metabolism, [SDV]Life Sciences [q-bio], Amino Acid Motifs, Lysosomes/chemistry/metabolism, hVPS45, Cathepsin D, Phosphatidylinositol 3-Kinases, Rab5, Carrier Proteins/*chemistry/genetics/*metabolism, Cloning, Molecular, Qa-SNARE Proteins, RING finger domain, MESH: rab5 GTP-Binding Proteins/metabolism, Protein Transport, MESH: Nerve Tissue Proteins/chemistry, Original Article, MESH: Lysosomes/chemistry, Membrane Proteins/chemistry/genetics/*metabolism, Protein Binding, Endosome, MESH: Membrane Microdomains/chemistry, Nerve Tissue Proteins, Biology, Cell Line, MESH: Membrane Proteins/genetics, Membrane Microdomains, MESH: Carrier Proteins/metabolism, endocytosis, MESH: Membrane Proteins/metabolism, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, 030304 developmental biology, rab5 GTP-Binding Proteins, MESH: Vesicular Transport Proteins, Sequence Homology, Amino Acid, MESH: Transfection, Membrane Proteins, MESH: Endosomes/metabolism, Cell Biology, MESH: Membrane Microdomains/metabolism, MESH: Lysosomes/metabolism, Membrane protein, MESH: Munc18 Proteins, MESH: Protein Processing, Post-Translational, MESH: HeLa Cells, Lysosomes, Protein Processing, Post-Translational, Sequence Alignment, Endosomes/chemistry/*metabolism
Abstract

International audience; Rab5 regulates endocytic membrane traffic by specifically recruiting cytosolic effector proteins to their site of action on early endosomal membranes. We have characterized a new Rab5 effector complex involved in endosomal fusion events. This complex includes a novel protein, Rabenosyn-5, which, like the previously characterized Rab5 effector early endosome antigen 1 (EEA1), contains an FYVE finger domain and is recruited in a phosphatidylinositol-3-kinase–dependent fashion to early endosomes. Rabenosyn-5 is complexed to the Sec1-like protein hVPS45. hVPS45 does not interact directly with Rab5, therefore Rabenosyn-5 serves as a molecular link between hVPS45 and the Rab5 GTPase. This property suggests that Rabenosyn-5 is a closer mammalian functional homologue of yeast Vac1p than EEA1. Furthermore, although both EEA1 and Rabenosyn-5 are required for early endosomal fusion, only overexpression of Rabenosyn-5 inhibits cathepsin D processing, suggesting that the two proteins play distinct roles in endosomal trafficking. We propose that Rab5-dependent formation of membrane domains enriched in phosphatidylinositol-3-phosphate has evolved as a mechanism for the recruitment of multiple effector proteins to mammalian early endosomes, and that these domains are multifunctional, depending on the differing activities of the effector proteins recruited.

Published
2000

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