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The activity of CARD9 is critically regulated by ubiquitination; however, the deubiquitinases involved in CARD9 regulation remain incompletely understood. In this study, we identified ovarian tumor deubiquitinase 1 (OTUD1) as an essential regulator of CARD9. OTUD1 directly interacted with CARD9 and cleaved polyubiquitin chains from CARD9, leading to the activation of the canonical NF-\u03baB and MAPK pathway. OTUD1 deficiency impaired CARD9-mediated signaling and inhibited the proinflammatory cytokine production following fungal stimulation. Importantly, Otud1\u2013\/\u2013 mice were more susceptible to fungal infection than wild-type mice in vivo. Collectively, our results identify OTUD1 as an essential regulatory component for the CARD9 signaling pathway and antifungal innate immunity through deubiquitinating CARD9.<\/jats:p>","DOI":"10.4049\/jimmunol.2001253","type":"journal-article","created":{"date-parts":[[2021,3,31]],"date-time":"2021-03-31T22:00:18Z","timestamp":1617228018000},"page":"1832-1843","source":"Crossref","is-referenced-by-count":26,"title":["OTUD1 Regulates Antifungal Innate Immunity through Deubiquitination of CARD9"],"prefix":"10.1093","volume":"206","author":[{"given":"Xiaorong","family":"Chen","sequence":"first","affiliation":[{"name":"Key Laboratory of Infection and Immunity of Shandong Province and Department of Immunology, School of Biomedical Sciences, Shandong University , 250012 Jinan, Shandong ,","place":["People\u2019s Republic of China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Honghai","family":"Zhang","sequence":"additional","affiliation":[{"name":"Key Laboratory of 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Shandong ,","place":["People\u2019s Republic of China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7228-5450","authenticated-orcid":false,"given":"Bingyu","family":"Liu","sequence":"additional","affiliation":[{"name":"Key Laboratory of Infection and Immunity of Shandong Province and Department of Immunology, School of Biomedical Sciences, Shandong University , 250012 Jinan, Shandong ,","place":["People\u2019s Republic of China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yi","family":"Zheng","sequence":"additional","affiliation":[{"name":"Key Laboratory of Infection and Immunity of Shandong Province and Department of Immunology, School of Biomedical Sciences, Shandong University , 250012 Jinan, Shandong ,","place":["People\u2019s Republic of China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tian","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Pathogenic Biology, 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