The NLRP3 inflammasome is a pivotal component of the innate immune system, responding to infections and cellular damage. Its dysregulation has been implicated in numerous inflammatory diseases, although the mechanisms controlling its activation remain incompletely elucidated. Recent studies have highlighted the importance of posttranslational modifications, such as ubiquitination and SUMOylation, in regulating inflammasome activation. In this study, we demonstrate that SENP6, a SUMO-specific protease, negatively regulates NLRP3 inflammasome activation by promoting K48-linked polyubiquitination of NLRP3. SENP6-deficient macrophages exhibit enhanced NLRP3 activation and increased secretion of interleukin-1β (IL-1β) and IL-18, resulting in amplified inflammatory responses. Mechanistically, SENP6 interacts with NLRP3 and promotes its degradation through the autophagy-lysosomal pathway via K48-linked polyubiquitination. We further identified that SENP6 deSUMOylated NLRP3 at specific lysine residues (K23, K204, and K689), which was essential for maintaining NLRP3 stability. Additionally, SENP6 recruits the E3 ubiquitin ligase MARCHF7 to promote NLRP3 ubiquitination and subsequent degradation. In vivo, SENP6 deficiency exacerbates NLRP3 activation and lung inflammation in lipopolysaccharide-induced endotoxic shock-associated lung injury, and enhances inflammatory responses in alum-induced peritonitis. Our findings reveal a novel mechanism whereby SENP6 modulates NLRP3 inflammasome activation via SUMOylation, ubiquitination, and degradation, providing new insights into potential therapeutic strategies for inflammasome-related pathologies.
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