biostudies-literatureZhang LChina Scholarship CouncilThe University of Texas MD Anderson Cancer CenterNIAID NIH HHSNCI NIH HHSNational Institutes of Health109904https://www.ebi.ac.uk/biostudies/studies/S-EPMC12011377biostudies-literatureUnknown37(4)Inflammasomes are crucial for innate immunity against infections and, when deregulated, also contribute to inflammatory diseases. Here, we identify a critical function of the E3 ubiquitin ligase Peli1 in regulating the activation of NLRP3 inflammasome. Peli1 deficiency impairs induction of interleukin-1β (IL-1β) secretion by different NLRP3 inducers, but not by inducers of the Aim2, NLRP1, and NLRC4 inflammasomes. Peli1-deficient mice have alleviated peritonitis induction by alum and display increased resistance to lipopolysaccharide (LPS) endotoxin shock, coupled with decreased serum concentration of IL-1β. Peli1 is required for NLRP3-induced caspase-1 activation and IL-1β maturation. Mechanistically, Peli1 conjugates K63 ubiquitin chain to lysine 55 of the inflammasome adaptor apoptosis-Cell reportsPeli1 facilitates NLRP3 inflammasome activation by mediating ASC ubiquitination.PMC12011377201906380080P30 CA016672AI057555R01 AI057555AI104519R01 AI104519Ko CJSun SCLi YJie ZXie XZhu LZhang LLiu TZhou XCheng XGao TfalsePeli1 facilitates NLRP3 inflammasome activation by mediating ASC ubiquitination.Inflammasomes are crucial for innate immunity against infections and, when deregulated, also contribute to inflammatory diseases. Here, we identify a critical function of the E3 ubiquitin ligase Peli1 in regulating the activation of NLRP3 inflammasome. Peli1 deficiency impairs induction of interleukin-1β (IL-1β) secretion by different NLRP3 inducers, but not by inducers of the Aim2, NLRP1, and NLRC4 inflammasomes. Peli1-deficient mice have alleviated peritonitis induction by alum and display increased resistance to lipopolysaccharide (LPS) endotoxin shock, coupled with decreased serum concentration of IL-1β. Peli1 is required for NLRP3-induced caspase-1 activation and IL-1β maturation. Mechanistically, Peli1 conjugates K63 ubiquitin chain to lysine 55 of the inflammasome adaptor apoptosis-2021-01-01T00:00:00Z2021 Oct2026-06-01T13:05:39.445Z2025-07-03T03:05:05.763ZS-EPMC120113773470623910.1016/j.celrep.2021.109904