SUMO1 Sumoylates and SENP3 DeSUMOylates NLRP3 to Orchestrate the Inflammasome Activation

Abstract

The NLRP3 inflammasome regulates innate immune and inflammatory responses by promoting caspase1-dependent induction of pro-inflammatory cytokines. However, aberrant inflammasome activation causes diverse diseases, and thus inflammasome activity must be tightly controlled. Here, we reveal a distinct mechanism underlying the regulation of NLRP3 inflammasome. NLRP3 interacts with SUMO-conjugating enzyme (UBC9) that subsequently promotes small ubiquitin-like modifier 1 (SUMO1) to catalyze NLRP3 SUMOylation. SUMO1 SUMOylates NLRP3 to promote ASC oligomerization, NLRP inflammasome activation, and interleukin-1β secretion. Additionally, SUMOylation residue K204 is critical for SUMO1-catalyzed NLRP3 SUMOylation and the inflammasome activation. Moreover, SUMO-specific protease 3 (SENP3) is required for the deSUMOylation of NLRP3. Interestingly, SENP3 deSUMOylates NLRP3 to attenuate ASC recruitment and speck formation, the NLRP3 inflammasome activation, and IL-1β cleavage and secretion. In conclusion, we reveal that SUMO1-catalyzed SUMOylation and SENP3-mediated deSUMOylation of NLRP3 orchestrate the inflammasome activation.