{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T19:43:20Z","timestamp":1790711000145,"version":"4.1.0"},"reference-count":50,"publisher":"Oxford University Press (OUP)","issue":"7","license":[{"start":{"date-parts":[[2020,4,1]],"date-time":"2020-04-01T00:00:00Z","timestamp":1585699200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/pages\/standard-publication-reuse-rights"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2020,4,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>IFN regulatory factor 3 (IRF3) is critical for the transcription of type I IFNs in defensing virus and promoting inflammatory responses. Although several kinds of posttranslational modifications have been identified to modulate the activity of IRF3, whether atypical ubiquitination participates in the function regulation, especially the DNA binding capacity of IRF3, is unknown. In this study, we found that the ovarian tumor domain containing deubiquitinase OTUD1 deubiquitinated IRF3 and attenuated its function. An atypical ubiquitination, K6-linked ubiquitination, was essential for the DNA binding capacity of IRF3 and subsequent induction of target genes. Mechanistically, OTUD1 cleaves the viral infection\u2013induced K6-linked ubiquitination of IRF3, resulting in the disassociation of IRF3 from the promoter region of target genes, without affecting the protein stability, dimerization, and nuclear translocation of IRF3 after a viral infection. Otud1\u2212\/\u2212 cells as well as Otud1\u2212\/\u2212 mice produced more type I IFNs and proinflammatory cytokines after viral infection. Otud1\u2212\/\u2212 mice were more resistant to lethal HSV-1 and VSV infection. Consistent with the former investigations that IRF3 promoted inflammatory responses in LPS-induced sepsis, Otud1\u2212\/\u2212 mice were more susceptible to LPS stimulation. Taken together, our findings revealed that the DNA binding capacity of IRF3 in the innate immune signaling pathway was modulated by atypical K6-linked ubiquitination and deubiquitination process, which was regulated by the deubiquitinase OTUD1.<\/jats:p>","DOI":"10.4049\/jimmunol.1900305","type":"journal-article","created":{"date-parts":[[2020,2,19]],"date-time":"2020-02-19T21:55:17Z","timestamp":1582149317000},"page":"1904-1918","source":"Crossref","is-referenced-by-count":80,"title":["OTUD1 Negatively Regulates Type I IFN Induction by Disrupting Noncanonical Ubiquitination of IRF3"],"prefix":"10.1093","volume":"204","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0307-5716","authenticated-orcid":false,"given":"Zeming","family":"Zhang","sequence":"first","affiliation":[{"name":"Department of Systems Biomedicine, School of Basic Medical Sciences, Peking University Health Science Center , Beijing 100191 ,","place":["China"]},{"name":"Institute of Systems Biomedicine, Beijing Key Laboratory of Tumor Systems Biology, Peking University Health Science Center , Beijing 100191 ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8643-2514","authenticated-orcid":false,"given":"Dandan","family":"Wang","sequence":"additional","affiliation":[{"name":"Institute of Systems Biomedicine, Beijing Key Laboratory of Tumor Systems Biology, Peking University Health Science Center , Beijing 100191 ,","place":["China"]},{"name":"Department of Immunology, School of Basic Medical Sciences, Peking University Health Science Center , Beijing 100191 ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peiyan","family":"Wang","sequence":"additional","affiliation":[{"name":"Institute of Systems Biomedicine, Beijing Key Laboratory of Tumor Systems Biology, Peking University Health Science Center , Beijing 100191 ,","place":["China"]},{"name":"Department of Immunology, School of Basic Medical Sciences, Peking University Health Science Center , Beijing 100191 ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yingchi","family":"Zhao","sequence":"additional","affiliation":[{"name":"Department of Systems Biomedicine, School of Basic Medical Sciences, Peking University Health Science Center , Beijing 100191 ,","place":["China"]},{"name":"Institute of Systems Biomedicine, Beijing Key Laboratory of Tumor Systems Biology, Peking University Health Science Center , Beijing 100191 ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7444-729X","authenticated-orcid":false,"given":"Fuping","family":"You","sequence":"additional","affiliation":[{"name":"Institute of Systems Biomedicine, Beijing Key Laboratory of Tumor Systems Biology, Peking University Health Science Center , Beijing 100191 ,","place":["China"]},{"name":"Department of Immunology, School of Basic Medical Sciences, Peking University Health Science Center , Beijing 100191 ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2020,4,1]]},"reference":[{"key":"2025030417511308100_r1","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1196\/annals.1443.020","article-title":"Toll-like receptor and RIG-I-like receptor signaling","volume":"1143","author":"Kawai","year":"2008","journal-title":"Ann. 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