11 results on '"Couté Y"'
Search Results
2. Cytoskeleton remodeling induced by SMYD2 methyltransferase drives breast cancer metastasis.
- Author
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Casanova AG, Roth GS, Hausmann S, Lu X, Bischoff LJM, Froeliger EM, Belmudes L, Bourova-Flin E, Flores NM, Benitez AM, Chasan T, Caporicci M, Vayr J, Blanchet S, Ielasi F, Rousseaux S, Hainaut P, Gozani O, Le Romancer M, Couté Y, Palencia A, Mazur PK, and Reynoird N
- Abstract
Malignant forms of breast cancer refractory to existing therapies remain a major unmet health issue, primarily due to metastatic spread. A better understanding of the mechanisms at play will provide better insights for alternative treatments to prevent breast cancer cell dispersion. Here, we identify the lysine methyltransferase SMYD2 as a clinically actionable master regulator of breast cancer metastasis. While SMYD2 is overexpressed in aggressive breast cancers, we notice that it is not required for primary tumor growth. However, mammary-epithelium specific SMYD2 ablation increases mouse overall survival by blocking the primary tumor cell ability to metastasize. Mechanistically, we identify BCAR3 as a genuine physiological substrate of SMYD2 in breast cancer cells. BCAR3 monomethylated at lysine K334 (K334me1) is recognized by a novel methyl-binding domain present in FMNLs proteins. These actin cytoskeleton regulators are recruited at the cell edges by the SMYD2 methylation signaling and modulate lamellipodia properties. Breast cancer cells with impaired BCAR3 methylation lose migration and invasiveness capacity in vitro and are ineffective in promoting metastases in vivo. Remarkably, SMYD2 pharmacologic inhibition efficiently impairs the metastatic spread of breast cancer cells, PDX and aggressive mammary tumors from genetically engineered mice. This study provides a rationale for innovative therapeutic prevention of malignant breast cancer metastatic progression by targeting the SMYD2-BCAR3-FMNL axis., (© 2024. The Author(s).)
- Published
- 2024
- Full Text
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3. In vitro production of cat-restricted Toxoplasma pre-sexual stages.
- Author
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Antunes AV, Shahinas M, Swale C, Farhat DC, Ramakrishnan C, Bruley C, Cannella D, Robert MG, Corrao C, Couté Y, Hehl AB, Bougdour A, Coppens I, and Hakimi MA
- Subjects
- Animals, Humans, Chromatin genetics, Chromatin metabolism, Disease Models, Animal, Epigenesis, Genetic, Merozoites genetics, Nuclear Proteins metabolism, Promoter Regions, Genetic genetics, Protozoan Proteins genetics, Protozoan Proteins metabolism, Toxoplasmosis genetics, Toxoplasmosis parasitology, Toxoplasmosis transmission, Transcription, Genetic, Cats parasitology, In Vitro Techniques methods, Life Cycle Stages genetics, Toxoplasma genetics, Toxoplasma growth & development, Toxoplasma physiology
- Abstract
Sexual reproduction of Toxoplasma gondii, confined to the felid gut, remains largely uncharted owing to ethical concerns regarding the use of cats as model organisms. Chromatin modifiers dictate the developmental fate of the parasite during its multistage life cycle, but their targeting to stage-specific cistromes is poorly described
1,2 . Here we found that the transcription factors AP2XII-1 and AP2XI-2 operate during the tachyzoite stage, a hallmark of acute toxoplasmosis, to silence genes necessary for merozoites, a developmental stage critical for subsequent sexual commitment and transmission to the next host, including humans. Their conditional and simultaneous depletion leads to a marked change in the transcriptional program, promoting a full transition from tachyzoites to merozoites. These in vitro-cultured pre-gametes have unique protein markers and undergo typical asexual endopolygenic division cycles. In tachyzoites, AP2XII-1 and AP2XI-2 bind DNA as heterodimers at merozoite promoters and recruit MORC and HDAC3 (ref.1 ), thereby limiting chromatin accessibility and transcription. Consequently, the commitment to merogony stems from a profound epigenetic rewiring orchestrated by AP2XII-1 and AP2XI-2. Successful production of merozoites in vitro paves the way for future studies on Toxoplasma sexual development without the need for cat infections and holds promise for the development of therapies to prevent parasite transmission., (© 2023. The Author(s).)- Published
- 2024
- Full Text
- View/download PDF
4. Membrane vesicles released by Lacticaseibacillus casei BL23 inhibit the biofilm formation of Salmonella Enteritidis.
- Author
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da Silva Barreira D, Laurent J, Lourenço J, Novion Ducassou J, Couté Y, Guzzo J, and Rieu A
- Subjects
- Lacticaseibacillus, Biofilms, Salmonella enteritidis, Lacticaseibacillus casei
- Abstract
Biofilms represent a major concern in the food industry and healthcare. The use of probiotic bacteria and their derivatives as an alternative to conventional treatments to fight biofilm development is a promising option that has provided convincing results in the last decades. Recently, membrane vesicles (MVs) produced by probiotics have generated considerable interest due to the diversity of roles they have been associated with. However, the antimicrobial activity of probiotic MVs remains to be studied. In this work, we showed that membrane vesicles produced by Lacticaseibacillus casei BL23 (LC-MVs) exhibited strong antibiofilm activity against Salmonella enterica serovar Enteritidis (S. Enteritidis) without affecting bacterial growth. Furthermore, we found that LC-MVs affected the early stages of S. Enteritidis biofilm development and prevented attachment of bacteria to polystyrene surfaces. Importantly, LC-MVs did not impact the biomass of already established biofilms. We also demonstrated that the antibiofilm activity depended on the proteins associated with the LC-MV fraction. Finally, two peptidoglycan hydrolases (PGHs) were found to be associated with the antibiofilm activity of LC-MVs. Overall, this work allowed to identify the antibiofilm properties of LC-MVs and paved the way for the use of probiotic MVs against the development of negative biofilms., (© 2023. The Author(s).)
- Published
- 2023
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5. Constrained G4 structures unveil topology specificity of known and new G4 binding proteins.
- Author
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Pipier A, Devaux A, Lavergne T, Adrait A, Couté Y, Britton S, Calsou P, Riou JF, Defrancq E, and Gomez D
- Subjects
- DNA-Binding Proteins metabolism, HeLa Cells, Humans, RNA Polymerase II chemistry, RNA Polymerase II metabolism, Transcription Factors chemistry, DNA-Binding Proteins chemistry, G-Quadruplexes, Oligonucleotides chemistry, Transcription Factors metabolism
- Abstract
G-quadruplexes (G4) are non-canonical secondary structures consisting in stacked tetrads of hydrogen-bonded guanines bases. An essential feature of G4 is their intrinsic polymorphic nature, which is characterized by the equilibrium between several conformations (also called topologies) and the presence of different types of loops with variable lengths. In cells, G4 functions rely on protein or enzymatic factors that recognize and promote or resolve these structures. In order to characterize new G4-dependent mechanisms, extensive researches aimed at identifying new G4 binding proteins. Using G-rich single-stranded oligonucleotides that adopt non-controlled G4 conformations, a large number of G4-binding proteins have been identified in vitro, but their specificity towards G4 topology remained unknown. Constrained G4 structures are biomolecular objects based on the use of a rigid cyclic peptide scaffold as a template for directing the intramolecular assembly of the anchored oligonucleotides into a single and stabilized G4 topology. Here, using various constrained RNA or DNA G4 as baits in human cell extracts, we establish the topology preference of several well-known G4-interacting factors. Moreover, we identify new G4-interacting proteins such as the NELF complex involved in the RNA-Pol II pausing mechanism, and we show that it impacts the clastogenic effect of the G4-ligand pyridostatin.
- Published
- 2021
- Full Text
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6. Apoptotic mesenchymal stromal cells support osteoclastogenesis while inhibiting multinucleated giant cells formation in vitro.
- Author
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Humbert P, Brennan MÁ, De Lima J, Brion R, Adrait A, Charrier C, Brulin B, Trichet V, Couté Y, Blanchard F, and Layrolle P
- Subjects
- Bone Marrow Cells physiology, Cell Proliferation, Cytokines, Giant Cells metabolism, Humans, Mesenchymal Stem Cells physiology, Osteoclasts physiology, Apoptosis, Bone Marrow Cells cytology, Cell Differentiation, Giant Cells pathology, Mesenchymal Stem Cells cytology, Osteoclasts cytology, Osteogenesis
- Abstract
In bone regeneration induced by the combination of mesenchymal stromal cells (MSCs) and calcium-phosphate (CaP) materials, osteoclasts emerge as a pivotal cell linking inflammation and bone formation. Favorable outcomes are observed despite short-term engraftments of implanted MSCs, highlighting their major paracrine function and the possible implication of cell death in modulating their secretions. In this work, we focused on the communication from MSCs towards osteoclasts-like cells in vitro. MSCs seeded on a CaP biomaterial or undergoing induced apoptosis produced a conditioned media favoring the development of osteoclasts from human CD14+ monocytes. On the contrary, MSCs' apoptotic secretion inhibited the development of inflammatory multinucleated giant cells formed after IL-4 stimulation. Components of MSCs' secretome before and after apoptotic stress were compared using mass spectrometry-based quantitative proteomics and a complementary immunoassay for major cytokines. CXCR-1 and CXCR-2 ligands, primarily IL-8/CXCL-8 but also the growth-regulated proteins CXCL-1, -2 or -3, were suggested as the major players of MSCs' pro-osteoclastic effect. These findings support the hypothesis that osteoclasts are key players in bone regeneration and suggest that apoptosis plays an important role in MSCs' effectiveness.
- Published
- 2021
- Full Text
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7. Structural and functional analysis of the Francisella lysine decarboxylase as a key actor in oxidative stress resistance.
- Author
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Felix J, Siebert C, Ducassou JN, Nigou J, Garcia PS, Fraudeau A, Huard K, Mas C, Brochier-Armanet C, Couté Y, Gutsche I, and Renesto P
- Subjects
- Amino Acid Sequence, Animals, Cells, Cultured, DNA Repair physiology, Escherichia coli metabolism, Macrophages metabolism, Mice, Proteomics methods, Sequence Alignment, Tularemia microbiology, Virulence physiology, Bacterial Proteins metabolism, Carboxy-Lyases metabolism, Francisella tularensis metabolism, Oxidative Stress physiology
- Abstract
Francisella tularensis is one of the most virulent pathogenic bacteria causing the acute human respiratory disease tularemia. While the mechanisms underlying F. tularensis pathogenesis are largely unknown, previous studies have shown that a F. novicida transposon mutant with insertions in a gene coding for a putative lysine decarboxylase was attenuated in mouse spleen, suggesting a possible role of its protein product as a virulence factor. Therefore, we set out to structurally and functionally characterize the F. novicida lysine decarboxylase, which we termed LdcF. Here, we investigate the genetic environment of ldcF as well as its evolutionary relationships with other basic AAT-fold amino acid decarboxylase superfamily members, known as key actors in bacterial adaptative stress response and polyamine biosynthesis. We determine the crystal structure of LdcF and compare it with the most thoroughly studied lysine decarboxylase, E. coli LdcI. We analyze the influence of ldcF deletion on bacterial growth under different stress conditions in dedicated growth media, as well as in infected macrophages, and demonstrate its involvement in oxidative stress resistance. Finally, our mass spectrometry-based quantitative proteomic analysis enables identification of 80 proteins with expression levels significantly affected by ldcF deletion, including several DNA repair proteins potentially involved in the diminished capacity of the F. novicida mutant to deal with oxidative stress. Taken together, we uncover an important role of LdcF in F. novicida survival in host cells through participation in oxidative stress response, thereby singling out this previously uncharacterized protein as a potential drug target.
- Published
- 2021
- Full Text
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8. A MORC-driven transcriptional switch controls Toxoplasma developmental trajectories and sexual commitment.
- Author
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Farhat DC, Swale C, Dard C, Cannella D, Ortet P, Barakat M, Sindikubwabo F, Belmudes L, De Bock PJ, Couté Y, Bougdour A, and Hakimi MA
- Subjects
- Adenosine Triphosphatases chemistry, Adenosine Triphosphatases metabolism, Animals, Cats, Chromatin, Fibroblasts parasitology, Histone Code, Histone Deacetylases chemistry, Histone Deacetylases metabolism, Histones genetics, Humans, Life Cycle Stages genetics, Models, Molecular, Primary Cell Culture, Protein Binding, Protein Processing, Post-Translational, Protein Structure, Secondary, Protozoan Proteins chemistry, Protozoan Proteins metabolism, Toxoplasma growth & development, Toxoplasma metabolism, Transcription Factors chemistry, Transcription Factors metabolism, Adenosine Triphosphatases genetics, Histone Deacetylases genetics, Histones metabolism, Protozoan Proteins genetics, Toxoplasma genetics, Transcription Factors genetics, Transcription, Genetic
- Abstract
Toxoplasma gondii has a complex life cycle that is typified by asexual development that takes place in vertebrates, and sexual reproduction, which occurs exclusively in felids and is therefore less studied. The developmental transitions rely on changes in the patterns of gene expression, and recent studies have assigned roles for chromatin shapers, including histone modifications, in establishing specific epigenetic programs for each given stage. Here, we identified the T. gondii microrchidia (MORC) protein as an upstream transcriptional repressor of sexual commitment. MORC, in a complex with Apetala 2 (AP2) transcription factors, was shown to recruit the histone deacetylase HDAC3, thereby impeding the accessibility of chromatin at the genes that are exclusively expressed during sexual stages. We found that MORC-depleted cells underwent marked transcriptional changes, resulting in the expression of a specific repertoire of genes, and revealing a shift from asexual proliferation to sexual differentiation. MORC acts as a master regulator that directs the hierarchical expression of secondary AP2 transcription factors, and these transcription factors potentially contribute to the unidirectionality of the life cycle. Thus, MORC plays a cardinal role in the T. gondii life cycle, and its conditional depletion offers a method to study the sexual development of the parasite in vitro, and is proposed as an alternative to the requirement of T. gondii infections in cats.
- Published
- 2020
- Full Text
- View/download PDF
9. The Toxoplasma effector TEEGR promotes parasite persistence by modulating NF-κB signalling via EZH2.
- Author
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Braun L, Brenier-Pinchart MP, Hammoudi PM, Cannella D, Kieffer-Jaquinod S, Vollaire J, Josserand V, Touquet B, Couté Y, Tardieux I, Bougdour A, and Hakimi MA
- Subjects
- Animals, Cell Line, Cell Nucleus metabolism, Cytokines metabolism, E2F Transcription Factors genetics, E2F Transcription Factors metabolism, Enhancer of Zeste Homolog 2 Protein genetics, Gene Expression, Gene Expression Regulation, Humans, Mice, Mice, Inbred BALB C, Mutation, Parasite Load, Promoter Regions, Genetic, Protein Multimerization, Protozoan Proteins genetics, Toxoplasma genetics, Toxoplasma immunology, Toxoplasmosis metabolism, Toxoplasmosis parasitology, Enhancer of Zeste Homolog 2 Protein metabolism, NF-kappa B metabolism, Protozoan Proteins metabolism, Signal Transduction genetics, Toxoplasma physiology
- Abstract
The protozoan parasite Toxoplasma gondii has co-evolved with its homeothermic hosts (humans included) strategies that drive its quasi-asymptomatic persistence in hosts, hence optimizing the chance of transmission to new hosts. Persistence, which starts with a small subset of parasites that escape host immune killing and colonize the so-called immune privileged tissues where they differentiate into a low replicating stage, is driven by the interleukin 12 (IL-12)-interferon-γ (IFN-γ) axis. Recent characterization of a family of Toxoplasma effectors that are delivered into the host cell, in which they rewire the host cell gene expression, has allowed the identification of regulators of the IL-12-IFN-γ axis, including repressors. We now report on the dense granule-resident effector, called TEEGR (Toxoplasma E2F4-associated EZH2-inducing gene regulator) that counteracts the nuclear factor-κB (NF-κB) signalling pathway. Once exported into the host cell, TEEGR ends up in the nucleus where it not only complexes with the E2F3 and E2F4 host transcription factors to induce gene expression, but also promotes shaping of a non-permissive chromatin through its capacity to switch on EZH2. Remarkably, EZH2 fosters the epigenetic silencing of a subset of NF-κB-regulated cytokines, thereby strongly contributing to the host immune equilibrium that influences the host immune response and promotes parasite persistence in mice.
- Published
- 2019
- Full Text
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10. V-erbA generates ribosomes devoid of RPL11 and regulates translational activity in avian erythroid progenitors.
- Author
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Nguyen-Lefebvre AT, Leprun G, Morin V, Viñuelas J, Couté Y, Madjar JJ, Gandrillon O, and Gonin-Giraud S
- Subjects
- Animals, Cell Transformation, Viral, Chickens, HSP70 Heat-Shock Proteins biosynthesis, HSP70 Heat-Shock Proteins genetics, Humans, RNA, Messenger genetics, RNA, Messenger metabolism, Ribosomal Proteins biosynthesis, Ribosomal Proteins genetics, Stem Cells metabolism, Transcription, Genetic, Erythrocytes cytology, Oncogene Proteins v-erbA genetics, Protein Biosynthesis, Ribosomal Proteins deficiency, Ribosomes genetics, Ribosomes metabolism, Stem Cells cytology
- Abstract
The v-erbA oncogene transforms chicken erythrocytic progenitors (T2EC) by blocking their differentiation and freezing them in a state of self-renewal. Transcriptomes of T2EC, expressing either v-erbA or a non-transforming form of v-erbA (S61G), were compared using serial analysis of gene expression and some, but not all, mRNA-encoding ribosomal proteins were seen to be affected by v-erbA. These results suggest that this oncogene could modulate the composition of ribosomes. In the present study, we demonstrate, using two-dimensional difference in gel electrophoresis, that v-erbA-expressing cells have a lower amount of RPL11 associated with the ribosomes. The presence of ribosomes devoid of RPL11 in v-erbA-expressing cells was further confirmed by immunoprecipitation. In order to assess the possible impact of these specialized ribosomes on the translational activity, we analyzed proteomes of either v-erbA or S61G-expressing cells using 2D/mass spectrometry, and identified nine proteins present in differing amounts within these cells. Among these proteins, we focused on HSP70 because of its involvement in erythroid differentiation. Our results indicate that, in v-erbA-expressing cells, hsp70 is not only transcribed but also translated more efficiently, as shown by polyribosome fractionation experiments. We demonstrate here, for the first time, the existence of ribosomes with different protein components, notably ribosomes devoid of RPL11, and a regulation of mRNA translation depending on v-erbA oncogene expression.
- Published
- 2014
- Full Text
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11. Unbalanced expression of CK2 kinase subunits is sufficient to drive epithelial-to-mesenchymal transition by Snail1 induction.
- Author
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Deshiere A, Duchemin-Pelletier E, Spreux E, Ciais D, Combes F, Vandenbrouck Y, Couté Y, Mikaelian I, Giusiano S, Charpin C, Cochet C, and Filhol O
- Subjects
- Breast Neoplasms genetics, Breast Neoplasms metabolism, Breast Neoplasms pathology, Carcinoma genetics, Carcinoma metabolism, Carcinoma pathology, Casein Kinase II metabolism, Casein Kinase II physiology, Cells, Cultured, Female, Gene Expression Profiling, Gene Expression Regulation, Neoplastic, Humans, Isoenzymes genetics, Isoenzymes metabolism, Microarray Analysis, Models, Biological, Protein Subunits genetics, Protein Subunits metabolism, Snail Family Transcription Factors, Tissue Array Analysis, Transcription Factors metabolism, Transcription Factors physiology, Up-Regulation genetics, Casein Kinase II genetics, Epithelial-Mesenchymal Transition genetics, Gene Expression Regulation, Enzymologic physiology, Transcription Factors genetics
- Abstract
Epithelial-to-mesenchymal transition (EMT) is closely linked to conversion of early-stage tumours into invasive malignancies. Many signalling pathways are involved in EMT, but the key regulatory kinases in this important process have not been clearly identified. Protein kinase CK2 is a multi-subunit protein kinase, which, when overexpressed, has been linked to disease progression and poor prognosis in various cancers. Specifically, overexpression of CK2α in human breast cancers is correlated with metastatic risk. In this article, we show that an imbalance of CK2 subunits reflected by a decrease in the CK2β regulatory subunit in a subset of breast tumour samples is correlated with induction of EMT-related markers. CK2β-depleted epithelial cells displayed EMT-like morphological changes, enhanced migration, and anchorage-independent growth, all of which require Snail1 induction. In epithelial cells, Snail1 stability is negatively regulated by CK2 and GSK3β through synergistic hierarchal phosphorylation. This process depends strongly on CK2β, thus confirming that CK2 functions upstream of Snail1. In primary breast tumours, CK2β underexpression also correlates strongly with expression of EMT markers, emphasizing the link between asymmetric expression of CK2 subunits and EMT in vivo. Our results therefore highlight the importance of CK2β in controlling epithelial cell plasticity. They show that CK2 holoenzyme activity is essential to suppress EMT, and that it contributes to maintaining a normal epithelial morphology. This study also suggests that unbalanced expression of CK2 subunits may drive EMT, thereby contributing to tumour progression.
- Published
- 2013
- Full Text
- View/download PDF
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