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Recent studies have revealed that NLRP3 K48\u2010linked ubiquitination by several E3 ligases, including Trim31, leads to degradation. Neddylation is a process highly similar to ubiquitination by covalently conjugating NEDD8 to lysines in specific substrate proteins. Neddylation of substrate proteins alters their subcellular localization, stability, and activity. The role of neddylation in the NLRP3 inflammasome remains elusive. Here, we report that neddylation promotes the activation of the NLRP3 inflammasome in macrophages. Myeloid deficiency of UBA3, the catalytic subunit of the NEDD8\u2010activating enzyme (NAE), renders mice resistant to dextran sodium sulfate\u2010induced colitis. Inducible\n                    <jats:italic>Uba3<\/jats:italic>\n                    deletion in microglia mitigates psychological stress\u2010induced anxiety\u2010like behavior. Neddylation blockade led to a reduced protein level of NLRP3 without affecting its mRNA level. Further exploration revealed that NLRP3 undergoes neddylation at K287 with Ube2M as the E2 and Smurf2 as an E3, respectively. NLRP3 neddylation hinders its interaction with Trim31 and thereby inhibits its K48\u2010linked ubiquitination and subsequent degradation. MLN4924, a potent compound NAE inhibitor in phase 1\/2\/3 clinical trials for cancers, alleviates psychological stress\u2010induced NLRP3 inflammasome activation, microglia inflammatory activation, and anxiety\u2010like behavior, suggesting novel clinical activity of MLN4924.\n                  <\/jats:p>","DOI":"10.1002\/advs.202505906","type":"journal-article","created":{"date-parts":[[2026,1,10]],"date-time":"2026-01-10T05:32:32Z","timestamp":1768023152000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Neddylation Targets and Stabilizes NLRP3 to Augment Inflammasome\u2010Mediated Colitis and Mood Disorder"],"prefix":"10.1002","volume":"13","author":[{"given":"Wenbin","family":"Gai","sequence":"first","affiliation":[{"name":"Beijing Institute of Basic Medical Sciences  Beijing 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