Membrane stress is coupled to a rapid translational control of gene expression in chlorpromazine-treated cells

Article Article scientifique Article Membrane stress is coupled to a rapid translational control of gene expression in chlorpromazine-treated cells eng 2007 author De Filippi Loic 134241 author Fournier Margot 134287 author Cameroni Elisabetta 505953 author Linder Patrick 61214 author De Virgilio Claudio 134289 author Foti Michelangelo 0000-0001-7199-4135 28033 author Deloche Olivier 28565 171-185 10.1007/s00294-007-0151-0 17710403 0172-8083 Chlorpromazine (CPZ) is a small permeable cationic amphiphilic molecule that inserts into membrane bilayers and binds to anionic lipids such as poly-phosphoinositides (PIs). Since PIs play important roles in many cellular processes, including signaling and membrane trafficking pathways, it has been proposed that CPZ affects cellular growth functions by preventing the recruitment of proteins with specific PI-binding domains. In this study, we have investigated the biological effects of CPZ in the yeast Saccharomyces cerevisiae. We screened a collection of approximately 4,800 gene knockout mutants, and found that mutants defective in membrane trafficking between the late-Golgi and endosomal compartments are highly sensitive to CPZ. Microscopy and transport analyses revealed that CPZ affects membrane structure of organelles, blocks membrane transport and activates the unfolded protein response (UPR). In addition, CPZ-treatment induces phosphorylation of the translation initiation factor (eIF2alpha), which reduces the general rate of protein synthesis and stimulates the production of Gcn4p, a major transcription factor that is activated in response to environmental stresses. Altogether, our results reveal that membrane stress within the cells rapidly activates an important gene expression program, which is followed by a general inhibition of protein synthesis. Remarkably, the increase of phosphorylated eIF2alpha and protein synthesis inhibition were also detected in CPZ-treated NIH-3T3 fibroblasts, suggesting the existence of a conserved mechanism of translational regulation that operates during a membrane stress. Animals Basic-Leucine Zipper Transcription Factors Blotting Northern Blotting Western Cell Membrane/ultrastructure Cell Proliferation/drug effects Chlorpromazine/pharmacology DNA-Binding Proteins/metabolism Dopamine Antagonists/pharmacology Endosomes Eukaryotic Initiation Factor-2/genetics/metabolism Fibroblasts Fluorescent Antibody Technique Gene Expression Regulation/drug effects Genome Fungal Golgi Apparatus Immunoprecipitation Mice NIH 3T3 Cells Peptide Chain Initiation Translational/drug effects Phosphorylation/drug effects Polyribosomes Protein Biosynthesis/drug effects Saccharomyces cerevisiae/drug effects/metabolism Saccharomyces cerevisiae Proteins/genetics/metabolism Transcription Factors/metabolism Beta-Galactosidase/metabolism Dewey 612 Dewey 616 Open Access - Licence nationale Springer 54 Département de microbiologie et médecine moléculaire 21B 134 Département de physiologie cellulaire et métabolisme 21C false 472 Obésité et syndrome métabolique 803 Current genetics 52 3-4 5db00482-448e-499f-a2fb-ee5f322a930a Article (Published version) Public De Filippi et al Curr Genet 2007.pdf 785772 application/pdf openAccess Faculté de médecine / Section de médecine fondamentale / Département de microbiologie et médecine moléculaire Faculté de médecine / Section de médecine fondamentale / Département de physiologie cellulaire et métabolisme

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Membrane stress is coupled to a rapid translational control of gene expression in chlorpromazine-treated cells	Current genetics			2007	548	385

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