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Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2026,2,24]]},"abstract":"<jats:p>The NLRP3 inflammasome is crucial for host defense against pathogen invasion and is implicated in various inflammatory disorders. The pathogenic association and the involved mechanism between the NLRP3 inflammasome and inflammatory diseases have garnered significant attention. Here, we demonstrate that Crohn\u2019s disease\u2013associated SNP RNF123-R854H aggravates colitis in vivo through the NLRP3-dependent pathway. Deficiency of RNF123 also aggravates dextran sodium sulfate-induced colitis, LPS (lipopolysaccharide)-induced endotoxemia, and Alum-induced peritonitis and enhances host defense against bacterial infection via the NLRP3-dependent pathway in vivo and promotes the NLRP3 inflammasome activation in cells. We establish RNF123 as a regulator for the NLRP3 inflammasome, highlighting its implication in the NLRP3 inflammasome-driven inflammatory diseases. Mechanistically, RNF123 catalyzes unanchored K63-linked ubiquitination of NEK7, thereby preventing NEK7-mediated dissociation of the inactive cage-like NLRP3 aggregates and the subsequent NLRP3 inflammasome assembly. Additionally, we prove that K63-linked polyubiquitin chains can be specifically captured by NEK7 in vitro and inhibit the NEK7-licensed NLRP3 inflammasome assembly. We propose that NEK7-captured unanchored K63-polyubiquitin chains serve as a key determinant for the NLRP3 inflammasome activation, acting as a molecular brake to limit the excessive NLRP3 inflammasome activation and preserve immune homeostasis. Our work yields mechanistic insights into the NLRP3 inflammasome regulation and its pathogenic link to inflammatory disease.<\/jats:p>","DOI":"10.1073\/pnas.2518759123","type":"journal-article","created":{"date-parts":[[2026,2,20]],"date-time":"2026-02-20T18:44:21Z","timestamp":1771613061000},"update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":1,"title":["The Crohn\u2019s disease\u2013related RNF123 prevents NLRP3 inflammasome assembly by catalyzing unanchored K63-linked ubiquitination on NEK7"],"prefix":"10.1073","volume":"123","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4589-5509","authenticated-orcid":false,"given":"Feng","family":"Liu","sequence":"first","affiliation":[{"name":"State Key Laboratory of Reproductive Medicine and Offspring Health, Key Laboratory of Infection Immunity and Disease Intervention of Shandong Province, Key Laboratory for Experimental Teratology of Ministry of Education, Shandong 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