The ubiquitin-specific protease USP8 directly deubiquitinates SQSTM1/p62 to suppress its autophagic activity |
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| Authors: | Hong Peng Fang Yang Qianwen Hu Jian Sun Cheng Peng Yao Zhao |
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| Institution: | 1. Shanghai Institute of Immunology &2. Department of Immunology and Microbiology, Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, Faculty of Basic Medicine, Shanghai Jiao Tong University School of Medicine, Shanghai, China;3. Laboratory of Medical Virology, School of Medicine, Sun Yat-sen University, Guangzhou, China;4. Department of Breast Surgery, Obstetrics and Gynecology Hospital, Fudan University, Shanghai, China;5. Department of Neurosurgery, Huashan Hospital, Shanghai Medical College, Fudan University, Shanghai, China |
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| Abstract: | ABSTRACTSQSTM1/p62 (sequestosome 1) is a critical macroautophagy/autophagy receptor that promotes the formation and degradation of ubiquitinated aggregates. SQSTM1 can be modified by ubiquitination, and this modification modulates its autophagic activity. However, the molecular mechanisms underpinning its reversible deubiquitination have never been described. Here we report that USP8 (ubiquitin specific peptidase 8) directly interacted with and deubiquitinated SQSTM1. USP8 preferentially removed the lysine 11 (K11)-linked ubiquitin chains from SQSTM1. Moreover, USP8 deubiquitinated SQSTM1 principally at K420 within its ubiquitin-association (UBA) domain. Finally, USP8 inhibited SQSTM1 degradation and autophagic influx in cells with wild-type SQSTM1, but not its mutant with substitution of K420 with an arginine. Taken together, USP8 acts as a negative regulator of autophagy by deubiquitinating SQSTM1 at K420.Abbreviations: BafA1: bafilomycin A1; BAP1: BRCA1 associated protein 1; DUB: deubiquitinating enzyme; ESCRT: endosomal sorting complex required for transport; HTT: huntingtin; K: lysine; KEAP1: kelch like ECH associated protein 1; MAP1LC3/LC3: microtubule associated protein 1 light chain 3; MEF: mouse embryonic fibroblast; shRNA: short hairpin RNA; SQSTM1: sequestosome 1; Ub: ubiquitin; UBA: ubiquitin-association; UBE2D2: ubiquitin conjugating enzyme E2 D2; UBE2D3: ubiquitin conjugating enzyme E2 D3; USP: ubiquitin specific peptidase; WT: wild-type |
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| Keywords: | Autophagy degradation SQSTM1/p62 ubiquitination USP8 |
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