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In this study, we identified the deubiquitinase USP22 as a positive regulator of TNF-R1. USP22 is minimally associated with TNF-R1, which is markedly increased following TNF stimulation. USP22 deconjugates K27-linked polyubiquitination of TNF-R1 at K340, which reverses its proteasomal degradation. USP22 deficiency reduces TNF-triggered signaling and transcriptional induction of proinflammatory genes in human cell lines and primary mouse immune cells. Conversely, the membrane-associated E3 ligase MARCH2 is constitutively associated with TNF-R1, resulting in K27-linked polyubiquitination of TNF-R1 at K340 and its proteasomal degradation. MARCH2 deficiency promotes TNF-triggered signaling in various cell types. In mice, USP22 deficiency alleviates imiquimod (IMQ)-induced psoriasis-like dermatitis with reduced inflammatory cell infiltration and splenomegaly. In an acute liver injury model, USP22 deficiency reduces TNF\/D-gal-induced inflammatory cytokine expression, liver damage, and inflammatory death, whereas MARCH2 deficiency increases TNF\/D-gal-induced inflammatory cytokine expression and exacerbates pathological features of acute liver injury. These findings demonstrate that MARCH2 and USP22 reciprocally regulate K27-linked polyubiquitination and stability of TNF-R1, revealing regulatory mechanisms on TNF-R1-mediated inflammatory response.<\/jats:p>","DOI":"10.1073\/pnas.2531389123","type":"journal-article","created":{"date-parts":[[2026,4,10]],"date-time":"2026-04-10T17:34:22Z","timestamp":1775842462000},"update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":1,"title":["Reciprocal regulation of TNF receptor 1\u2013mediated signaling and inflammatory damages by MARCH2 and USP22"],"prefix":"10.1073","volume":"123","author":[{"given":"Hui-Fang","family":"Li","sequence":"first","affiliation":[{"name":"Department of Infectious Diseases, State Key Laboratory of Virology and Biosafety, Frontier Science Center for Immunology and Metabolism, Medical Research Institute, Zhongnan Hospital of Wuhan University, Taikang Center for Life and Medical Sciences, Wuhan 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