ABRO1 stabilizes the deubiquitinase BRCC3 through inhibiting its degradation mediated by the E3 ubiquitin ligase WWP2

Abstract

BRCA1/BRCA2‐containing complex subunit 3 (BRCC3) is a lysine 63‐specific deubiquitinase involved in multiple biological processes, such as DNA repair and immune responses. However, the regulation mechanism for BRCC3 protein stability is still unknown. Here, we demonstrate that BRCC3 is mainly degraded through the ubiquitin‐proteasome pathway. The HECT‐type E3 ubiquitin ligase WWP2 modulates BRCC3 ubiquitination and degradation. ABRO1, a subunit of the BRCC36 isopeptidase complex (BRISC), competes with WWP2 to bind to BRCC3, thereby preventing WWP2‐mediated BRCC3 ubiquitination and enhancing BRCC3 stability. Functionally, we show that lentivirus‐mediated overexpression of WWP2 in murine macrophages inhibits NLRP3 inflammasome activation by decreasing BRCC3 protein level. This study provides the first insights into the regulation of BRCC3 stability and expands our knowledge about the physiological function of WWP2.

The deubiquitinating enzyme complex BRISC regulates Aurora B activation via lysine-63-linked ubiquitination in mitosis

“…2a ), and the efficiency of the knockout was confirmed by Western blotting. Consistent with the previous report 40 , knockout of either BRCC36 or Abro1 dramatically disturbed the stability of the other one in the BRISC complex (Supplementary Fig. 2b ), while the protein level of Aurora B was not obviously affected, as detected by Western blotting (Supplementary Fig.…”

The roles of ubiquitination and deubiquitination of NLRP3 inflammasome in inflammation-related diseases: A review

“…Additionally, lentivirus-mediated overexpression of E3 Ub ligase WWP2 in LPS- and Nigerian mycobacteria-induced mouse BMDMs reduced BRCA1/BRCA2-containing complex subunit 3 (BRCC3) protein levels in DUBs. This reduction inhibited the deubiquitylation modification of NLRP3 inflammasomes, leading to their degradation and consequently inhibiting the inflammatory response [ 53 ]. In another study, the knockdown of DUB USP30 in advanced glycation end products (AGEs)-treated human skin fibroblast model inhibited the NLRP3 inflammasome deubiquitination.…”

The Role of Post-Translational Modifications in Regulation of NLRP3 Inflammasome Activation

“…Ubiquitin C-terminal hydrolase L5 (UCHL5) contributes to the inflammasome activation via elimination of K63-linked ubiquitin chains on NLRP3 [ 46 ]. Abraxas brother 1 (ABRO1), a subunit of the BRCA1/BRCA2-containing complex subunit 36 (BRCC36) isopeptidase complex (BRISC), impedes WW domain-containing E3 ubiquitin-protein ligase 2 (WWP2)-mediated BRCC3 ubiquitination and increases BRCC3 stability [ 69 ]. BRCC3 deubiquitinates NLRP3 LRR domain and positively regulates NLRP3 inflammasome activation [ 70 ].…”