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3. Dual Fractions Proteomic Analysis of Silica Nanoparticle Interactions with Protein Extracts.

Author

Schvartz, Marion, Saudrais, Florent, Boulard, Yves, Renault, Jean-Philippe, Henry, Céline, Chédin, Stéphane, Pin, Serge, and Aude, Jean-Christophe

Subjects
SILICA nanoparticles, SILICA analysis, NANOPARTICLES, SACCHAROMYCES cerevisiae, MASS spectrometry
Abstract

Dual-fraction proteomics reveals a novel class of proteins impacted by nanoparticle exposure. Background: Nanoparticles (NPs) interact with cellular proteomes, altering biological processes. Understanding these interactions requires comprehensive analyses beyond solely characterizing the NP corona. Methods: We utilized a dual-fraction mass spectrometry (MS) approach to analyze both NP-bound and unbound proteins in Saccharomyces cerevisiae sp. protein extracts exposed to silica nanoparticles (SiNPs). We identified unique protein signatures for each fraction and quantified protein abundance changes using spectral counts. Results: Strong correlations were observed between protein profiles in each fraction and non-exposed controls, while minimal correlation existed between the fractions themselves. Linear models demonstrated equal contributions from both fractions in predicting control sample abundance. Combining both fractions revealed a larger proteomic response to SiNP exposure compared to single-fraction analysis. We identified 302/56 proteins bound/unbound to SiNPs and an additional 196 "impacted" proteins demonstrably affected by SiNPs. Conclusion: This dual-fraction MS approach provides a more comprehensive understanding of nanoparticle interactions with cellular proteomes. It reveals a novel class of "impacted" proteins, potentially undergoing conformational changes or aggregation due to NP exposure. Further research is needed to elucidate their biological functions and the mechanisms underlying their impact. [ABSTRACT FROM AUTHOR]

Published
2024
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4. Role of the Protein Corona in the Colloidal Behavior of Microplastics

Author

Schvartz, Marion, primary, Saudrais, Florent, additional, Devineau, Stéphanie, additional, Chédin, Stéphane, additional, Jamme, Frédéric, additional, Leroy, Jocelyne, additional, Rakotozandriny, Karol, additional, Taché, Olivier, additional, Brotons, Guillaume, additional, Pin, Serge, additional, Boulard, Yves, additional, and Renault, Jean-Philippe, additional

Published
2023
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8. Protein Corona Composition of Silica Nanoparticles in Complex Media: Nanoparticle Size does not Matter

Author

Marichal, Laurent, Klein, Géraldine, Armengaud, Jean, Boulard, Yves, Chédin, Stéphane, Labarre, Jean, Pin, Serge, Renault, Jean-Philippe, Aude, Jean-Christophe, 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), Laboratoire Interdisciplinaire sur l'Organisation Nanométrique et Supramoléculaire (LIONS), Nanosciences et Innovation pour les Matériaux, la Biomédecine et l'Energie (ex SIS2M) (NIMBE UMR 3685), Institut Rayonnement Matière de Saclay (IRAMIS), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Institut Rayonnement Matière de Saclay (IRAMIS), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Procédés Alimentaires et Microbiologiques [Dijon] (PAM), Université de Bourgogne (UB)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Université Bourgogne Franche-Comté [COMUE] (UBFC), Laboratoire Innovations technologiques pour la Détection et le Diagnostic (LI2D), Service de Pharmacologie et Immunoanalyse (SPI), Médicaments et Technologies pour la Santé (MTS), Université Paris-Saclay-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)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Université Paris-Saclay-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)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Médicaments et Technologies pour la Santé (MTS), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), 'Programme de Toxicologie' (NaToM grant) of the CEA, Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Institut de Chimie du CNRS (INC)-Institut Rayonnement Matière de Saclay (IRAMIS), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Institut de Chimie du CNRS (INC), and Université Bourgogne Franche-Comté [COMUE] (UBFC)-Université de Bourgogne (UB)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement

Subjects
lcsh:Chemistry, endocrine system, protein corona, lcsh:QD1-999, high-throughput proteomics, curvature effect, Bayesian statistical analysis, [CHIM.MATE]Chemical Sciences/Material chemistry, silica nanoparticles, Article
Abstract

International audience; Biomolecules, and particularly proteins, bind on nanoparticle (NP) surfaces to form the so-called protein corona. It is accepted that the corona drives the biological distribution and toxicity of NPs. Here, the corona composition and structure were studied using silica nanoparticles (SiNPs) of different sizes interacting with soluble yeast protein extracts. Adsorption isotherms showed that the amount of adsorbed proteins varied greatly upon NP size with large NPs having more adsorbed proteins per surface unit. The protein corona composition was studied using a large-scale label-free proteomic approach, combined with statistical and regression analyses. Most of the proteins adsorbed on the NPs were the same, regardless of the size of the NPs. To go beyond, the protein physicochemical parameters relevant for the adsorption were studied: electrostatic interactions and disordered regions are the main driving forces for the adsorption on SiNPs but polypeptide sequence length seems to be an important factor as well. This article demonstrates that curvature effects exhibited using model proteins are not determining factors for the corona composition on SiNPs, when dealing with complex biological media.

Published
2020
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9. Importance of Post-translational Modifications in the Interaction of Proteins with Mineral Surfaces: The Case of Arginine Methylation and Silica surfaces

Author

Marichal, Laurent, primary, Renault, Jean-Philippe, additional, Chédin, Stéphane, additional, Lagniel, Gilles, additional, Klein, Géraldine, additional, Aude, Jean-Christophe, additional, Tellier-Lebegue, Carine, additional, Armengaud, Jean, additional, Pin, Serge, additional, Labarre, Jean, additional, and Boulard, Yves, additional

Published
2018
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11. Characterization of the oxidative stress response in yeast cells protected by gamma-glutamylcysteine instead of glutathione

Author

Hatem, Elie, Lagniela, Gilles, Jean-Jacques, Hélène, Labarre, Jean, Kuras, Laurent, and Chédin, Stéphane

Abstract

Redox homeostasis is achieved by antioxidant systems, involving a large collection of enzymes that scavenge or degrade Reactive Oxygen Species (ROS) produced endogenously at low levels during cell growth. Besides the enzymatic protection against ROS, cells also contain small antioxidant molecules, such as glutathione (GSH). With an intracellular concentration between 1 and 10 mM, GSH is the most abundant non-protein thiol in the cell and is considered as the major redox buffer of the cell. In a previous study, we showed that only scarce amounts of intracellular GSH are required to protect yeast nuclear activities during oxidative stress. Surprisingly, such protection is sufficient for cell survival despite the strong oxidation of cytosolic proteins and the complete inhibition of protein synthesis (Hatem et al., 2014). GSH synthesis is a two-step process involving the gamma-glutamylcysteine (g-GC) synthetase Gsh1, which produces the g-GC intermediate from glutamate and cysteine, and the glutathione synthetase Gsh2, which adds a glycine to g-GC to release the final tripeptide. Deletion of GSH2 leads to yeast cells accumulating abnormal amounts of g-GC. It has been suggested that this molecule could replace GSH during oxidative stress exposure as the viability of ∆gsh2 cells, unable to synthesize GSH, is only mildly affected in oxidative stress conditions. Because our previous study revealed that the antioxidant protection of all cellular components and activities is not strictly required to preserve cell viability during oxidative stress, we decided to better characterize the physiological response of ∆gsh2 cells submitted to hydrogen peroxide treatments. Here we present the main results of this study and discuss the potential role of g-GC in the cellular protection against oxidative injury, compare to GSH., Journal of International Society of Antioxidants in Nutrition & Health, Vol 3, No 3 (2016)

Published
2016
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12. Protein folding activity of the ribosome: Key player in yeast prion propagation

Author

Voisset, Cecile P., Blondel, Marc, Soubigou, Flavie, Evrard, Justine, Nguyen, Phu Hai, Hassin, Naushaba, Chédin, Stéphane, Gillet, Reynald, Contesse, Marie-Astrid, Friocourt, Gaëlle, Stahl, Guillaume, Jones, Gary, Génétique, génomique fonctionnelle et biotechnologies (UMR 1078) (GGB), Institut Brestois Santé Agro Matière (IBSAM), Université de Brest (UBO)-Université de Brest (UBO)-EFS-Institut National de la Santé et de la Recherche Médicale (INSERM), Hôpital Morvan [Brest], National University of Ireland Maynooth (Maynooth University), Service de Biologie Intégrative et Génétique Moléculaire (SBIGeM), 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)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS), Institut Universitaire de France (IUF), Ministère de l'Education nationale, de l’Enseignement supérieur et de la Recherche (M.E.N.E.S.R.), Institut de Génétique et Développement de Rennes (IGDR), Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Centre National de la Recherche Scientifique (CNRS)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Sciences et ingénierie en biologie santé (SCINBIOS), Université de Brest (UBO)-Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratoire de Génétique Moléculaire et d'Histocompatibilité [Brest], Hôpital Morvan [Brest]-Centre Hospitalier Régional Universitaire de Brest (CHRU Brest), Laboratoire de biologie moléculaire eucaryote (LBME), Centre National de la Recherche Scientifique (CNRS)-Centre de Biologie Intégrative (CBI), Université Toulouse III - Paul Sabatier (UT3), 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-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS), Génétique, génomique fonctionnelle et biotechnologies (UMR 1078), EFS-Université de Brest ( UBO ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), National University of Ireland Maynooth ( NUIM ), Service de Biologie Intégrative et Génétique Moléculaire ( SBIGeM ), Institut de Biologie Intégrative de la Cellule ( I2BC ), Université Paris-Sud - Paris 11 ( UP11 ) -Commissariat à l'énergie atomique et aux énergies alternatives ( CEA ) -Université Paris-Saclay-Centre National de la Recherche Scientifique ( CNRS ) -Université Paris-Sud - Paris 11 ( UP11 ) -Commissariat à l'énergie atomique et aux énergies alternatives ( CEA ) -Université Paris-Saclay-Centre National de la Recherche Scientifique ( CNRS ), Institut Universitaire de France ( IUF ), Ministère de l'Éducation nationale, de l’Enseignement supérieur et de la Recherche ( M.E.N.E.S.R. ), Institut de Génétique et Développement de Rennes ( IGDR ), Université de Rennes 1 ( UR1 ), Université de Rennes ( UNIV-RENNES ) -Université de Rennes ( UNIV-RENNES ) -Centre National de la Recherche Scientifique ( CNRS ) -Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Sciences et ingénierie en biologie santé ( SCINBIOS ), Université de Brest ( UBO ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Centre Hospitalier Régional Universitaire de Brest ( CHRU Brest ) -Hôpital Morvan [Brest], Laboratoire de biologie moléculaire eucaryote du CNRS ( LBME ), Université Paul Sabatier - Toulouse 3 ( UPS ) -Centre National de la Recherche Scientifique ( CNRS ), EFS-Université de Brest (UBO)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Brestois Santé Agro Matière (IBSAM), Université de Brest (UBO), 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 ), Université de Toulouse (UT)-Université de Toulouse (UT)-Centre National de la Recherche Scientifique (CNRS)-Centre de Biologie Intégrative (CBI), and Université de Toulouse (UT)-Université de Toulouse (UT)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS)

Subjects
[ SDV ] Life Sciences [q-bio], [SDV]Life Sciences [q-bio], ComputingMilieux_MISCELLANEOUS
Abstract

International audience; Meeting Abstract: O-04

Published
2016
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14. RNA-binding proteins are a major target of silica nanoparticles in cell extracts

Author

Klein, Géraldine, primary, Mathé, Christelle, additional, Biola-Clier, Mathilde, additional, Devineau, Stéphanie, additional, Drouineau, Emilie, additional, Hatem, Elie, additional, Marichal, Laurent, additional, Alonso, Béatrice, additional, Gaillard, Jean-Charles, additional, Lagniel, Gilles, additional, Armengaud, Jean, additional, Carrière, Marie, additional, Chédin, Stéphane, additional, Boulard, Yves, additional, Pin, Serge, additional, Renault, Jean-Philippe, additional, Aude, Jean-Christophe, additional, and Labarre, Jean, additional

Published
2016
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15. Protein Folding Activity of the Ribosome is involved in Yeast Prion Propagation

Author

Blondel, Marc, primary, Soubigou, Flavie, additional, Evrard, Justine, additional, Nguyen, Phu hai, additional, Hasin, Naushaba, additional, Chédin, Stéphane, additional, Gillet, Reynald, additional, Contesse, Marie-Astrid, additional, Friocourt, Gaëlle, additional, Stahl, Guillaume, additional, Jones, Gary W., additional, and Voisset, Cécile, additional

Published
2016
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16. H2O2 activates the nuclear localization of Msn2 and Maf1 through thioredoxins in yeast

Author

Boisnard, Stéphanie, Lagniel, Gilles, Garmendia-Torres, Cecilia, Molin, Mikael, Boy-Marcotte, Emmanuelle, Jacquet, Michel, Toledano, Michel B, Labarre, Jean, Chédin, Stéphane, Institut de génétique et microbiologie [Orsay] (IGM), and Université Paris-Sud - Paris 11 (UP11)-Centre National de la Recherche Scientifique (CNRS)

Subjects
[SDV.MP]Life Sciences [q-bio]/Microbiology and Parasitology, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology
Abstract

International audience; The cellular response to hydrogen peroxide (H2O2) is characterized by a repression of growth-related processes and an enhanced expression of genes important for cell defense. In budding yeast, this response requires the activation of a set of transcriptional effectors. Some of them, such as the transcriptional activator Yap1, are specific to oxidative stress and others, such as the transcriptional activators Msn2/4 and the negative regulator Maf1, are activated by a wide spectrum of stress conditions. How these general effectors are activated in response to oxidative stress remains an open question. In this study, we demonstrate that the two cytoplasmic thioredoxins, Trx1 and Trx2, are essential to trigger the nuclear accumulation of Msn2/4 and Maf1, specifically under H2O2 treatment. Contrarily to many stress conditions previously described in yeast, the H2O2-induced nuclear accumulation of Msn2 and Maf1 does not correlate with the down-regulation of PKA kinase activity. Nevertheless, we show that the PP2A phosphatase activity is essential for driving Maf1 dephosphorylation and its subsequent nuclear accumulation in response to H2O2 treatment. Interestingly, under this condition, the lack of PP2A activity has no impact on the subcellular localization of Msn2, demonstrating that the H2O2 signaling pathways share a common route through the thioredoxin system and then diverge to activate Msn2 and Maf1, the final integrators of these pathways.

Published
2009
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17. Protein folding activity of ribosomal rna is a selective target of two unrelated antiprion drugs

Author

Tribouillard-Tanvier, Déborah, Reis, Suzana Dos, Gug, Fabienne, Voisset, Cécile, Béringue, Vincent, Sabate, Raimon, Kikovska, Ema, Talarek, Nicolas, Bach, Stéphane, Huang, Chenhui, Desban, Nathalie, Saupe, Sven J., Supattapone, Surachai, Thuret, Jean-Yves, Chédin, Stéphane, Vilette, Didier, Galons, Hervé, Sanyal, Suparna, Blondel, Marc, Tribouillard-Tanvier, Déborah, Reis, Suzana Dos, Gug, Fabienne, Voisset, Cécile, Béringue, Vincent, Sabate, Raimon, Kikovska, Ema, Talarek, Nicolas, Bach, Stéphane, Huang, Chenhui, Desban, Nathalie, Saupe, Sven J., Supattapone, Surachai, Thuret, Jean-Yves, Chédin, Stéphane, Vilette, Didier, Galons, Hervé, Sanyal, Suparna, and Blondel, Marc

Abstract

Background: 6-Aminophenanthridine (6AP) and Guanabenz (GA, a drug currently in use for the treatment of hypertension) were isolated as antiprion drugs using a yeast-based assay. These structurally unrelated molecules are also active against mammalian prion in several cell-based assays and in vivo in a mouse model for prion-based diseases.Methodology/Principal Findings: Here we report the identification of cellular targets of these drugs. Using affinity chromatography matrices for both drugs, we demonstrate an RNA-dependent interaction of 6AP and GA with the ribosome. These specific interactions have no effect on the peptidyl transferase activity of the ribosome or on global translation. In contrast, 6AP and GA specifically inhibit the ribosomal RNA-mediated protein folding activity of the ribosome.Conclusion/Significance: 6AP and GA are therefore the first compounds to selectively inhibit the protein folding activity of the ribosome. They thus constitute precious tools to study the yet largely unexplored biological role of this protein folding activity.

Published
2010

19. Is ribosome synthesis controlled by pol I transcription?

Author

Chédin, Stéphane, Laferté, Arnaud, Hoang, Tran, Lafontaine, Denis, Riva, Michel, Carles, Christophe, Chédin, Stéphane, Laferté, Arnaud, Hoang, Tran, Lafontaine, Denis, Riva, Michel, and Carles, Christophe

Abstract

Regulation of growth ultimately depends on the control of synthesis of new ribosomes. Ribosome biogenesis is thus a key element of cell biology, which is tightly regulated in response to environmental conditions. In eukaryotic cells, the supply of ribosomal components involves the activities of the three forms of nuclear RNA polymerase (Pol I, Pol II and Pol III). Recently, we demonstrated that upon rapamycin treatment, a partial derepression of Pol I transcription led to a concomitant derepression of Pol II transcription restricted to a small subset of class II genes encompassing the genes encoding all ribosomal proteins, and 19 additional genes. The products of 14 of these 19 genes are principally involved in rDNA structure, ribosome biogenesis or translation, whereas the five remaining genes code for hypothetical proteins. We demonstrate that the proteins encoded by these five genes are required for optimal pre-rRNA processing. In addition, we show that cells in which regulation of Pol I transcription was specifically impaired are either resistant or hypersensitive to different stresses compared to wild-type cells. These results highlight the critical role of the regulation of Pol I activity for the physiology of the cells., Journal Article, Research Support, Non-U.S. Gov't, Review, info:eu-repo/semantics/published

Published
2007

22. Protein Folding Activity of Ribosomal RNA Is a Selective Target of Two Unrelated Antiprion Drugs

Author

Tribouillard-Tanvier, Déborah, primary, Dos Reis, Suzana, additional, Gug, Fabienne, additional, Voisset, Cécile, additional, Béringue, Vincent, additional, Sabate, Raimon, additional, Kikovska, Ema, additional, Talarek, Nicolas, additional, Bach, Stéphane, additional, Huang, Chenhui, additional, Desban, Nathalie, additional, Saupe, Sven J., additional, Supattapone, Surachai, additional, Thuret, Jean-Yves, additional, Chédin, Stéphane, additional, Vilette, Didier, additional, Galons, Hervé, additional, Sanyal, Suparna, additional, and Blondel, Marc, additional

Published
2008
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27. H2O2Activates the Nuclear Localization of Msn2 and Maf1 through Thioredoxins in Saccharomyces cerevisiae

Author

Boisnard, Stéphanie, Lagniel, Gilles, Garmendia-Torres, Cecilia, Molin, Mikael, Boy-Marcotte, Emmanuelle, Jacquet, Michel, Toledano, Michel B., Labarre, Jean, and Chédin, Stéphane

Abstract

The cellular response to hydrogen peroxide (H2O2) is characterized by a repression of growth-related processes and an enhanced expression of genes important for cell defense. In budding yeast, this response requires the activation of a set of transcriptional effectors. Some of them, such as the transcriptional activator Yap1, are specific to oxidative stress, and others, such as the transcriptional activators Msn2/4 and the negative regulator Maf1, are activated by a wide spectrum of stress conditions. How these general effectors are activated in response to oxidative stress remains an open question. In this study, we demonstrate that the two cytoplasmic thioredoxins, Trx1 and Trx2, are essential to trigger the nuclear accumulation of Msn2/4 and Maf1, specifically under H2O2treatment. Contrary to the case with many stress conditions previously described for yeast, the H2O2-induced nuclear accumulation of Msn2 and Maf1 does not correlate with the downregulation of PKA kinase activity. Nevertheless, we show that PP2A phosphatase activity is essential for driving Maf1 dephosphorylation and its subsequent nuclear accumulation in response to H2O2treatment. Interestingly, under this condition, the lack of PP2A activity has no impact on the subcellular localization of Msn2, demonstrating that the H2O2signaling pathways share a common route through the thioredoxin system and then diverge to activate Msn2 and Maf1, the final integrators of these pathways.

Published
2009

28. Protein folding activity of ribosomal rna is a selective target of two unrelated antiprion drugs

Author

Tribouillard-Tanvier, Déborah, Reis, Suzana Dos, Gug, Fabienne, Voisset, Cécile, Béringue, Vincent, Sabate, Raimon, Kikovska, Ema, Talarek, Nicolas, Bach, Stéphane, Huang, Chenhui, Desban, Nathalie, Saupe, Sven J., Supattapone, Surachai, Thuret, Jean-Yves, Chédin, Stéphane, Vilette, Didier, Galons, Hervé, Sanyal, Suparna, Blondel, Marc, Tribouillard-Tanvier, Déborah, Reis, Suzana Dos, Gug, Fabienne, Voisset, Cécile, Béringue, Vincent, Sabate, Raimon, Kikovska, Ema, Talarek, Nicolas, Bach, Stéphane, Huang, Chenhui, Desban, Nathalie, Saupe, Sven J., Supattapone, Surachai, Thuret, Jean-Yves, Chédin, Stéphane, Vilette, Didier, Galons, Hervé, Sanyal, Suparna, and Blondel, Marc

Abstract

Background: 6-Aminophenanthridine (6AP) and Guanabenz (GA, a drug currently in use for the treatment of hypertension) were isolated as antiprion drugs using a yeast-based assay. These structurally unrelated molecules are also active against mammalian prion in several cell-based assays and in vivo in a mouse model for prion-based diseases.Methodology/Principal Findings: Here we report the identification of cellular targets of these drugs. Using affinity chromatography matrices for both drugs, we demonstrate an RNA-dependent interaction of 6AP and GA with the ribosome. These specific interactions have no effect on the peptidyl transferase activity of the ribosome or on global translation. In contrast, 6AP and GA specifically inhibit the ribosomal RNA-mediated protein folding activity of the ribosome.Conclusion/Significance: 6AP and GA are therefore the first compounds to selectively inhibit the protein folding activity of the ribosome. They thus constitute precious tools to study the yet largely unexplored biological role of this protein folding activity.

29. H2O2 activates the nuclear localization of Msn2 and Maf1 through thioredoxins in Saccharomyces cerevisiae.

Author

Boisnard S, Lagniel G, Garmendia-Torres C, Molin M, Boy-Marcotte E, Jacquet M, Toledano MB, Labarre J, and Chédin S

Subjects
Cell Nucleus genetics, DNA-Binding Proteins genetics, Membrane Proteins genetics, Peroxiredoxins genetics, Protein Transport, Saccharomyces cerevisiae genetics, Saccharomyces cerevisiae Proteins genetics, Thioredoxins genetics, Transcription Factors genetics, Cell Nucleus metabolism, DNA-Binding Proteins metabolism, Hydrogen Peroxide metabolism, Membrane Proteins metabolism, Peroxiredoxins metabolism, Saccharomyces cerevisiae metabolism, Saccharomyces cerevisiae Proteins metabolism, Thioredoxins metabolism, Transcription Factors metabolism
Abstract

The cellular response to hydrogen peroxide (H(2)O(2)) is characterized by a repression of growth-related processes and an enhanced expression of genes important for cell defense. In budding yeast, this response requires the activation of a set of transcriptional effectors. Some of them, such as the transcriptional activator Yap1, are specific to oxidative stress, and others, such as the transcriptional activators Msn2/4 and the negative regulator Maf1, are activated by a wide spectrum of stress conditions. How these general effectors are activated in response to oxidative stress remains an open question. In this study, we demonstrate that the two cytoplasmic thioredoxins, Trx1 and Trx2, are essential to trigger the nuclear accumulation of Msn2/4 and Maf1, specifically under H(2)O(2) treatment. Contrary to the case with many stress conditions previously described for yeast, the H(2)O(2)-induced nuclear accumulation of Msn2 and Maf1 does not correlate with the downregulation of PKA kinase activity. Nevertheless, we show that PP2A phosphatase activity is essential for driving Maf1 dephosphorylation and its subsequent nuclear accumulation in response to H(2)O(2) treatment. Interestingly, under this condition, the lack of PP2A activity has no impact on the subcellular localization of Msn2, demonstrating that the H(2)O(2) signaling pathways share a common route through the thioredoxin system and then diverge to activate Msn2 and Maf1, the final integrators of these pathways.

Published
2009
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