Key Points USP39 stabilizes STAT1 protein level. USP39 as deubiquitinase can reduce the K6-linked ubiquitination of STAT1. USP39 can sustain type I IFN–induced antiviral immunity. Deubiquitinating enzymes (DUBs) are cysteine proteases that reverse the ubiquitination by removing ubiquitins from the target protein. The human genome encodes ∼100 potential DUBs, which can be classified into six families, influencing multiple cellular processes, such as antiviral responses, inflammatory responses, apoptosis, etc. To systematically explore the role of DUBs involved in antiviral immunity, we performed an RNA interference–based screening that contains 97 human DUBs. We identified that ubiquitin-specific protease (USP) 39 expression modulates the antiviral activity, which is, to our knowledge, a previously unknown function of this enzyme. Small interfering RNA knockdown of USP39 significantly enhanced viral replication, whereas overexpression of USP39 had an opposite effect. Mechanistically, USP39 does not affect the production of type I IFN but significantly promotes JAK/STAT downstream of type I signaling by enhancing IFN-stimulated response elements promoter activity and expression of IFN-stimulated genes. Interestingly, USP39, previously considered not to have the deubiquitinase activity, in this study is proved to interact with STAT1 and sustain its protein level by deubiqutination. Furthermore, we found that through novel mechanism USP39 can significantly decrease K6-linked but not K48-linked ubiquitination of STAT1 for degradation. Taken together, these findings uncover that USP39 is, to our knowledge, a new deubiquitinase that positively regulates IFN-induced antiviral efficacy.

中文翻译：

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USP39 作为去泛素化酶稳定 STAT1 并维持 I 型干扰素诱导的抗病毒免疫

要点 USP39 稳定 STAT1 蛋白水平。USP39 作为去泛素化酶可以减少 K6 连接的 STAT1 泛素化。USP39 可以维持 I 型干扰素诱导的抗病毒免疫。去泛素化酶 (DUB) 是半胱氨酸蛋白酶，可通过从靶蛋白中去除泛素来逆转泛素化。人类基因组编码约 100 个潜在的 DUB，可分为六个家族，影响多个细胞过程，如抗病毒反应、炎症反应、细胞凋亡等。 为了系统地探索 DUB 在抗病毒免疫中的作用，我们进行了 RNA基于干扰的筛选，包含 97 个人类 DUB。我们发现泛素特异性蛋白酶 (USP) 39 表达调节抗病毒活性，据我们所知，这是该酶以前未知的功能。USP39 的小干扰 RNA 敲低显着增强了病毒复制，而 USP39 的过度表达具有相反的效果。从机制上讲，USP39 不影响 I 型 IFN 的产生，但通过增强 IFN 刺激的反应元件启动子活性和 IFN 刺激基因的表达，显着促进 I 型信号传导下游的 JAK/STAT。有趣的是，之前被认为不具有去泛素化酶活性的 USP39 在本研究中被证明与 STAT1 相互作用并通过去泛素化维持其蛋白质水平。此外，我们发现通过新机制 USP39 可以显着降低 K6-linked 而不是 K48-linked 的 STAT1 泛素化降解。总之，这些发现揭示了 USP39，据我们所知，