title: USP14 regulates autophagy by suppressing K63 ubiquitination of Beclin 1.
abstract: The ubiquitin-proteasome system (UPS) and autophagy are two major intracellular degradative mechanisms that mediate the turnover of complementary repertoires of intracellular proteomes. Simultaneously activating both UPS and autophagy might provide a powerful strategy for the clearance of misfolded proteins. However, it is not clear whether UPS and autophagy can be controlled by a common regulatory mechanism. K48 deubiquitination by USP14 is known to inhibit UPS. Here we show that USP14 regulates autophagy by negatively controlling K63 ubiquitination of Beclin 1. Furthermore, we show that activation of USP14 by Akt-mediated phosphorylation provides a mechanism for Akt to negatively regulate autophagy by promoting K63 deubiquitination. Our study suggests that Akt-regulated USP14 activity modulates both proteasomal degradation and autophagy through controlling K48 and K63 ubiquitination, respectively. Therefore, regulation of USP14 provides a mechanism for Akt to control both proteasomal and autophagic degradation. We propose that inhibition of USP14 may provide a strategy to promote both UPS and autophagy for developing novel therapeutics targeting neurodegenerative diseases.
authors.affiliation: Interdisciplinary Research Center on Biology and Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai 201210, China;
authors.forename: Daichao
authors.initials: D
authors.lastname: Xu
authors.affiliation: Interdisciplinary Research Center on Biology and Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai 201210, China;
authors.forename: Bing
authors.initials: B
authors.lastname: Shan
authors.affiliation: Interdisciplinary Research Center on Biology and Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai 201210, China;
authors.forename: Huawang
authors.initials: H
authors.lastname: Sun
authors.affiliation: Interdisciplinary Research Center on Biology and Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai 201210, China;
authors.forename: Juan
authors.initials: J
authors.lastname: Xiao
authors.affiliation: Interdisciplinary Research Center on Biology and Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai 201210, China;
authors.forename: Kezhou
authors.initials: K
authors.lastname: Zhu
authors.affiliation: Interdisciplinary Research Center on Biology and Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai 201210, China;
authors.forename: Xingxing
authors.initials: X
authors.lastname: Xie
authors.affiliation: Interdisciplinary Research Center on Biology and Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai 201210, China;
authors.forename: Xingyan
authors.initials: X
authors.lastname: Li
authors.affiliation: Interdisciplinary Research Center on Biology and Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai 201210, China;
authors.forename: Wei
authors.initials: W
authors.lastname: Liang
authors.affiliation: Interdisciplinary Research Center on Biology and Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai 201210, China;
authors.forename: Xiaojuan
authors.initials: X
authors.lastname: Lu
authors.affiliation: Interdisciplinary Research Center on Biology and Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai 201210, China;
authors.forename: Lihui
authors.initials: L
authors.lastname: Qian
authors.affiliation: Interdisciplinary Research Center on Biology and Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai 201210, China; Department of Cell Biology, Harvard Medical School, Boston, Massachusetts 02115, USA.
authors.forename: Junying
authors.initials: J
authors.lastname: Yuan
mesh_terms: D001343:Autophagy / Q000502:physiology*; D000071186:Beclin-1 / Q000378:metabolism*; D058546:Class III Phosphatidylinositol 3-Kinases / Q000378:metabolism; D015870:Gene Expression; D057809:HEK293 Cells; D006801:Humans; D051058:Oncogene Protein v-akt / Q000378:metabolism; D010766:Phosphorylation; D043222:Ubiquitin Thiolesterase / Q000235:genetics / Q000378:metabolism*; D054875:Ubiquitination
chemical_list: D000071186:Beclin-1; C509299:USP14 protein, human; D058546:Class III Phosphatidylinositol 3-Kinases; D051058:Oncogene Protein v-akt; D043222:Ubiquitin Thiolesterase
keywords: Akt; Beclin 1; USP14; autophagy