The Deubiquitinating Enzyme USP20 Regulates the TNF?-Induced NF-?B Signaling Pathway through Stabilization of p62.

ABSTRACT: p62/sequestosome-1 is a scaffolding protein involved in diverse cellular processes such as autophagy, oxidative stress, cell survival and death. It has been identified to interact with atypical protein kinase Cs (aPKCs), linking these kinases to NF-?B activation by tumor necrosis factor ? (TNF?). The diverse functions of p62 are regulated through post-translational modifications of several domains within p62. Among the enzymes that mediate these post-translational modifications, little is known about the deubiquitinating enzymes (DUBs) that remove ubiquitin chains from p62, compared to the E3 ligases involved in p62 ubiquitination. In this study, we first demonstrate a role of ubiquitin-specific protease USP20 in regulating p62 stability in TNF?-mediated NF-?B activation. USP20 specifically binds to p62 and acts as a positive regulator for NF-?B activation by TNF? through deubiquitinating lysine 48 (K48)-linked polyubiquitination, eventually contributing to cell survival. Furthermore, depletion of USP20 disrupts formation of the atypical PKC?-RIPK1-p62 complex required for TNF?-mediated NF-?B activation and significantly increases the apoptosis induced by TNF? plus cycloheximide or TNF? plus TAK1 inhibitor. These findings strongly suggest that the USP20-p62 axis plays an essential role in NF-?B-mediated cell survival induced by the TNF?-atypical PKC? signaling pathway.

SUBMITTER: Ha J 

PROVIDER: S-EPMC7247158 | biostudies-literature | 2020 Apr

REPOSITORIES: biostudies-literature