Herpes Simplex Virus 1 Ubiquitin-Specific Protease UL36 Inhibits Beta Interferon Production by Deubiquitinating TRAF3
Herpes Simplex Virus 1 Ubiquitin-Specific Protease UL36 Inhibits Beta Interferon Production by Deubiquitinating TRAF3
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DOI：
10.1128/jvi.01211-13
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发表时间：
2013-08
影响因子：
5.4
通讯作者：
Shuai Wang;Kezhen Wang;Jie Li;C. Zheng
中科院分区：
文献类型：
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作者：
Shuai Wang;Kezhen Wang;Jie Li;C. Zheng
**摘要** 干扰素（IFN）介导的天然免疫防御是一种强大的抗病毒机制。病毒会逃避天然免疫并限制β干扰素（IFN-β）的分泌，以便在宿主体内复制和存活。单纯疱疹病毒1型（HSV-1）最大的包膜蛋白UL36，在其N端含有一个新的去泛素化酶（DUB）基序，称为UL36泛素特异性蛋白酶（UL36USP）。在本研究中，我们证明HSV-1的UL36USP可抑制仙台病毒（SeV）诱导的干扰素调节因子3（IRF3）二聚化、启动子激活以及IFN-β的转录。UL36USP的去泛素化酶活性对于阻断IFN-β的产生至关重要。UL36USP还能抑制由维甲酸诱导基因I（RIG-I）N端（RIG-IN）和线粒体抗病毒信号蛋白（MAVS）过表达所诱导的IFN-β启动子活性，但对TANK结合激酶1（TBK-1）、IκB激酶ε（IKKε）以及IRF3/5D诱导的启动子活性无抑制作用。随后发现，UL36USP可去除肿瘤坏死因子受体相关因子3（TRAF3）上的多聚泛素链，并阻止下游衔接蛋白TBK1的募集。我们构建了缺乏UL36USP去泛素化酶活性的重组HSV-1。与野生型（WT）HSV-1感染的细胞相比，感染该突变病毒的细胞产生更多的IFN-β。这些研究结果表明，HSV-1的UL36USP可去除TRAF3上的多聚泛素链，从而对抗IFN-β通路。
ABSTRACT Interferon (IFN)-mediated innate immune defense is a potent antiviral mechanism. Viruses evade innate immunity and limit secretion of beta interferon (IFN-β) to replicate and survive in the host. The largest tegument protein of herpes simplex virus 1 (HSV-1), UL36, contains a novel deubiquitinase (DUB) motif embedded in its N terminus, denoted UL36 ubiquitin-specific protease (UL36USP). In the present study, we demonstrate that HSV-1 UL36USP inhibits Sendai virus (SeV)-induced interferon regulatory factor 3 (IRF3) dimerization, promoter activation, and transcription of IFN-β. The DUB activity of UL36USP is essential to block IFN-β production. UL36USP also inhibited IFN-β promoter activity induced by overexpression of the N terminus of RIG-I (RIG-IN) and MAVS, but not TBK-1, IκB kinase ε (IKKε), and IRF3/5D. UL36USP was subsequently shown to deubiquitinate TRAF3 and prevent the recruitment of the downstream adaptor TBK1. The recombinant HSV-1 lacking UL36USP DUB activity was generated. Cells infected with the mutant virus produced more IFN-β than wild-type (WT) HSV-1-infected cells. These findings demonstrate HSV-1 UL36USP removes polyubiquitin chains on TRAF3 and counteracts the IFN-β pathway.