Type-I interferons (IFN-I) are used as common antiviral drugs for a range of viral diseases in clinic. However, the antiviral efficacy of IFN-I is largely restricted by negative regulators of IFN-I signaling in cells. Therefore, identification of intracellular inhibitors of IFN-I signaling is important for developing novel targets to improve IFN-I antiviral therapy. In this study, we report that the deubiquitinase ubiquitin-specific protease 7 (USP7) negatively regulates IFN-I-mediated 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-I-induced activation of Janus kinase-signal transducer and activator of transcription 1 signaling. Interestingly, viral infection up-regulates USP7 and therefore facilitates viral immune evasion. Importantly, the USP7 small-molecule inhibitors P5091 and P22077 inhibit SOCS1 expression and enhance IFN-I antiviral efficacy. Our findings identify a novel regulator of IFN-I antiviral activity and reveal that USP7 inhibitors could be potential enhancement agents for improving IFN-I antiviral therapy.

中文翻译：

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泛素特异性蛋白酶7的小分子抑制剂通过使SOCS1不稳定来增强I型干扰素的抗病毒功效。

I型干扰素（IFN-I）在临床上用作多种病毒性疾病的常用抗病毒药物。然而，IFN-1的抗病毒功效在很大程度上受到细胞中IFN-1信号转导的负调节剂的限制。因此，鉴定细胞内IFN-I信号抑制剂对于开发改善IFN-I抗病毒治疗的新靶标很重要。在这项研究中，我们报告说，去泛素酶泛素特异性蛋白酶7（USP7）负调控IFN-I介导的抗病毒活性。USP7与细胞因子信号转导1（SOCS1）的抑制剂发生物理相互作用，并通过去泛素化作用增强SOCS1蛋白的稳定性，这反过来又限制了IFN-I诱导的Janus激酶信号转导子和转录1信号转导子的激活。有趣的是 病毒感染会上调USP7，从而促进病毒免疫逃逸。重要的是，USP7小分子抑制剂P5091和P22077抑制SOCS1表达并增强IFN-1抗病毒功效。我们的发现确定了一种新型的IFN-I抗病毒活性调节剂，并揭示了USP7抑制剂可能是改善IFN-I抗病毒治疗的潜在增强剂。