title: Acetylation of translationally controlled tumor protein promotes its degradation through chaperone-mediated autophagy.
abstract: Translationally controlled tumor protein (Tpt1/TCTP) is a multi-functional cytosolic protein whose cellular levels are finely tuned. TCTP regulates protein behavior by favoring stabilization of protein partners or on the contrary by promoting degradation of others. TCTP has been shown to be transcriptionally and translationally regulated, but much less is known about its degradation process. In this study, we present evidence that chaperone-mediated autophagy (CMA) contributes to TCTP regulation. CMA allows lysosomal degradation of specific cytosolic proteins on a molecule-by-molecule basis. It contributes to cellular homeostasis especially by acting as a quality control for cytosolic proteins in response to stress and as a way of regulating the level of specific proteins. Using a variety of approaches, we show that CMA degradation of TCTP is Hsc70 and LAMP-2A dependent. Our data indicate that (i) TCTP directly interacts with Hsc70; (ii) silencing LAMP-2A in MEFs using siRNA leads to inhibition of TCTP downregulation; (iii) TCTP is relocalized from a diffuse cytosolic pattern to a punctate lysosomal pattern when CMA is upregulated; (iv) TCTP is degraded in vitro by purified lysosomes. Importantly, using lysine-mutated forms of TCTP, we show that acetylation of Lysine 19 generates a KFERQ-like motif and promotes binding to Hsc70, lysosome targeting and TCTP degradation by CMA. Altogether these results indicate that TCTP is degraded by chaperone-mediated autophagy in an acetylation dependent manner.
authors.affiliation: UMR 5235, CNRS, Université Montpellier, 34095 Montpellier, France.
authors.forename: Anne
authors.initials: A
authors.lastname: Bonhoure
authors.affiliation: UMR 5235, CNRS, Université Montpellier, 34095 Montpellier, France.
authors.forename: Alice
authors.initials: A
authors.lastname: Vallentin
authors.affiliation: UMR 5235, CNRS, Université Montpellier, 34095 Montpellier, France.
authors.forename: Marianne
authors.initials: M
authors.lastname: Martin
authors.affiliation: UMR 8113, École Normale Supérieure, 94235 Cachan, France; UMR 981, Institut Gustave Roussy, 94800 Villejuif, France.
authors.forename: Andrea
authors.initials: A
authors.lastname: Senff-Ribeiro
authors.affiliation: UMR 8113, École Normale Supérieure, 94235 Cachan, France; UMR 981, Institut Gustave Roussy, 94800 Villejuif, France.
authors.forename: Robert
authors.initials: R
authors.lastname: Amson
authors.affiliation: UMR 8113, École Normale Supérieure, 94235 Cachan, France; UMR 981, Institut Gustave Roussy, 94800 Villejuif, France.
authors.forename: Adam
authors.initials: A
authors.lastname: Telerman
authors.affiliation: UMR 5235, CNRS, Université Montpellier, 34095 Montpellier, France. Electronic address: michel.vidal@umontpellier.fr.
authors.forename: Michel
authors.initials: M
authors.lastname: Vidal
mesh_terms: D000107:Acetylation; D000818:Animals; D001343:Autophagy / Q000502:physiology*; D014408:Biomarkers, Tumor / Q000378:metabolism*; D001943:Breast Neoplasms / Q000378:metabolism; D015536:Down-Regulation; D005347:Fibroblasts / Q000378:metabolism; D018840:HSP70 Heat-Shock Proteins / Q000378:metabolism; D006367:HeLa Cells; D006801:Humans; D008247:Lysosomes / Q000378:metabolism; D061986:MCF-7 Cells; D053858:Metabolic Networks and Pathways; D051379:Mice; D018832:Molecular Chaperones / Q000378:metabolism; D009363:Neoplasm Proteins / Q000378:metabolism; D011499:Protein Processing, Post-Translational; D059748:Proteolysis; D000090324:Tumor Protein, Translationally-Controlled 1
chemical_list: D014408:Biomarkers, Tumor; D018840:HSP70 Heat-Shock Proteins; D018832:Molecular Chaperones; D009363:Neoplasm Proteins; C000715647:TPT1 protein, human; C000715648:Tpt1 protein, mouse; D000090324:Tumor Protein, Translationally-Controlled 1
keywords: Acetylation; Autophagy; Chaperone; Lysosome; Proteolysis; Subcellular fractionation