The ubiquitin-specific protease USP8 directly deubiquitinates SQSTM1/p62 to suppress its autophagic activity.

The ubiquitin-specific protease USP8 directly deubiquitinates SQSTM1/p62 to suppress its autophagic activity.
Autophagy. 2019 Jun 26;:
Authors: Peng H, Yang F, Hu Q, Sun J, Peng C, Zhao Y, Huang C
Abstract
SQSTM1/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.
PMID: 31241013 [PubMed - as supplied by publisher]

Source: Autophagy - June 25, 2019 Category: Cytology Authors: Peng H, Yang F, Hu Q, Sun J, Peng C, Zhao Y, Huang C Tags: Autophagy Source Type: research