USP39 Serves as a Deubiquitinase to Stabilize STAT1 and Sustains Type I IFN-Induced Antiviral Immunity
USP39 Serves as a Deubiquitinase to Stabilize STAT1 and Sustains Type I IFN-Induced Antiviral Immunity
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USP39 作为去泛素酶来稳定 STAT1 并维持 I 型 IFN 诱导的抗病毒免疫
DOI：
10.4049/jimmunol.1901384
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发表时间：
2020-12-01
影响因子：
4.4
通讯作者：
Xiong, Sidong
中科院分区：
文献类型：
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作者：
Peng, Yihong;Guo, Jing;Xiong, Sidong
脱泛素化酶(DUBS)是半胱氨酸蛋白酶，通过从目标蛋白质中去除泛素来逆转泛素化。人类基因组编码100个潜在的DUBS，可分为6个家族，影响多种细胞过程，如抗病毒反应、炎症反应、细胞凋亡等。为了系统地探索DUBS在抗病毒免疫中的作用，我们进行了一项基于RNA干扰的筛选，其中包含97个人类DUB。我们发现泛素特异性蛋白水解酶(USP)39的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。小干扰RNA敲除USP39可显著促进病毒复制，而过表达USP39则相反。从机制上讲，USP39不影响I型干扰素的产生，但通过增强干扰素刺激的反应元件启动子活性和干扰素刺激基因的表达而显著促进I型信号转导下游的JAK/STAT。有趣的是，此前被认为不具有脱泛素酶活性的USP39，在本研究中被证明与STAT1相互作用，并通过脱泛素来维持其蛋白质水平。此外，我们发现通过新的机制，USP39可以显著减少K6连接的但不是K48连接的STAT1的泛素化降解。综上所述，这些发现揭示了，据我们所知，USP39是一种新的去泛素酶，它积极地调节干扰素诱导的抗病毒疗效。
Deubiquitinating enzymes (DUBs) are cysteine proteases that reverse the ubiquitination by removing ubiquitins from the target protein. The human genome encodes similar to 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.