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However, the antiviral efficacy of IFN\u2010I is largely restricted by negative regulators of IFN\u2010I signaling in cells. Therefore, identification of intracellular inhibitors of IFN\u2010I signaling is important for developing novel targets to improve IFN\u2010I antiviral therapy. In this study, we report that the deubiquitinase ubiquitin\u2010specific protease 7 (USP7) negatively regulates IFN\u2010I\u2010mediated antiviral activity. USP7 physically interacts with suppressor of cytokine signaling 1 (SOCS1) and enhances SOCS1 protein stability by deubiquitination effects, which in turn restricts IFN\u2010I\u2010induced activation of Janus kinase\u2013signal transducer and activator of transcription 1 signaling. Interestingly, viral infection up\u2010regulates USP7 and therefore facilitates viral immune evasion. Importantly, the USP7 small\u2010molecule inhibitors P5091 and P22077 inhibit SOCS1 expression and enhance IFN\u2010I antiviral efficacy. Our findings identify a novel regulator of IFN\u2010I antiviral activity and reveal that USP7 inhibitors could be potential enhancement agents for improving IFN\u2010I antiviral therapy.<\/jats:p>","DOI":"10.1111\/imm.13147","type":"journal-article","created":{"date-parts":[[2019,11,6]],"date-time":"2019-11-06T06:40:39Z","timestamp":1573022439000},"page":"309-321","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":15,"title":["Small\u2010molecule inhibitors of ubiquitin\u2010specific protease 7 enhance type\u2010I interferon antiviral efficacy by destabilizing SOCS1"],"prefix":"10.1111","volume":"159","author":[{"given":"Yukang","family":"Yuan","sequence":"first","affiliation":[{"name":"Institutes of Biology and Medical Sciences Jiangsu Key Laboratory of Infection and Immunity Soochow University Suzhou 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