Journal
EUROPEAN JOURNAL OF CELL BIOLOGY
Volume 96, Issue 2, Pages 83-98Publisher
ELSEVIER GMBH
DOI: 10.1016/j.ejcb.2016.12.002
Keywords
Acetylation; Autophagy; Chaperone; Lysosome; Proteolysis; Subcellular fractionation
Categories
Funding
- Agence Nationale de la Recherche [ANR-09-BLAN-0292-01]
- Labex LERMIT
- Ligue Contre Le Cancer
- CNRS, University of Montpellier
- Science Without Borders
- NICHD
- Odyssea
- Institut National du Cancer
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Translationally controlled tumor protein (Tptl/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. (C) 2016 Elsevier GmbH. All rights reserved.
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