The E3 ubiquitin ligase TRIM31 attenuates NLRP3 inflammasome activation by promoting proteasomal degradation of NLRP3

Abstract

The NLRP3 inflammasome has a fundamental role in host defence against microbial pathogens and its deregulation may cause diverse inflammatory diseases. NLRP3 protein expression is a rate-limiting step for inflammasome activation, thus its expression must be tightly controlled to maintain immune homeostasis and avoid detrimental effects. However, how NLRP3 expression is regulated remains largely unknown. In this study, we identify E3 ubiquitin ligase TRIM31 as a feedback suppressor of NLRP3 inflammasome. TRIM31 directly binds to NLRP3, promotes K48-linked polyubiquitination and proteasomal degradation of NLRP3. Consequently, TRIM31 deficiency enhances NLRP3 inflammasome activation and aggravates alum-induced peritonitis in vivo. Furthermore, TRIM31 deficiency attenuates the severity of dextran sodium sulfate (DSS)-induced colitis, an inflammatory bowel diseases model in which NLRP3 possesses protective roles. Thus, our research describes a mechanism by which TRIM31 limits NLRP3 inflammasome activity under physiological conditions and suggests TRIM31 as a potential therapeutic target for the intervention of NLRP3 inflammasome related diseases.

SUMO1 SUMOylates and SENP3 deSUMOylates NLRP3 to orchestrate the inflammasome activation

“…The NLRP3 inflammasome activation is regulated by phosphorylation, 16 ubiquitination, 17,43 and SUMOylation. The NLRP3 inflammasome activation is regulated by phosphorylation, 16 ubiquitination, 17,43 and SUMOylation.…”

NLRP3, un inflammasome sous contrôle

“…La désensibilisation de NLRP3, après un long engagement de certains des récepteurs de priming, repose sur des modifications qui l'altèrent. Ainsi, l'E3 ligase TRIM31 (tripartite motif containing 31), induite par le lipopolysaccharide bactérien (LPS) et l'IL-1, induit l'ubiquitination de NLRP3 avec des chaînes K48, ce qui conduit à sa dégradation par le protéasome [51]. La sécrétion autocrine/paracrine d'IFN-I conduit à la production de NO, en activant l'iNOS (inducible nitric oxyde synthase) responsable de la S-nitrosylation de NLRP3 au niveau de son domaine LRR riche en cystéines, qui inhibe l'assemblage de l'inflammasome [22].…”

Loss-of-function CARD8 mutation causes NLRP3 inflammasome activation and Crohn’s disease

“…Recent studies have provided evidence that serine phosphorylation of NLRP3 mediated by phosphokinase A (PKA) inhibits NLRP3 inflammasome activation and that such phosphorylation is disrupted in CAPS patients with increased NLRP3 inflammasome activity (13). In addition, it has been reported that NLRP3 polyubiquitination also inhibits NLRP3 inflammasome activation (14,15). It is therefore possible that the inhibitory effect of intact CARD8 and to immunoprecipitation with anti-NLRP3 antibody and then immunoblotting with anti-phosphoserine antibody as described above.…”