USP3 inhibits type I interferon signaling by deubiquitinating RIG-I-like receptors
USP3 inhibits type I interferon signaling by deubiquitinating RIG-I-like receptors
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USP3 通过去泛素化 RIG-I 样受体来抑制 I 型干扰素信号传导。
DOI：
10.1038/cr.2013.170
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发表时间：
2014-04-01
期刊：
影响因子：
44.1
通讯作者：
Wang, Rong-Fu
中科院分区：
文献类型：
--
作者：
Cui, Jun;Song, Yanxia;Wang, Rong-Fu
赖氨酸63 （K63）连接的RIG-I泛素化在I型干扰素途径的激活中起着关键作用，但其去泛素化的分子机制仍然知之甚少。在这里，我们报道了去泛素化酶泛素特异性蛋白酶3 （USP3）通过靶向rig - 1负性调节I型干扰素信号的激活。USP3的下调特异性地增强了k63连接的RIG-I泛素化，上调了IRF3的磷酸化，增强了I型干扰素细胞因子的产生和抗病毒免疫。我们进一步发现，在未刺激或未感染的细胞中，USP3与rig - i样受体（RLRs）之间没有相互作用，但在病毒感染或配体刺激下，USP3结合到RLRs的caspase激活募集结构域，然后通过其锌指ub结合结构域和USP催化结构域的合作，切割多泛素链。突变分析表明，USP3与rig - 1上的多泛素链结合是其切割多泛素链的先决条件。我们的研究结果确定了USP3在RIG-I激活中以前未被认识到的作用，并为USP3抑制RIG-I信号传导和抗病毒免疫的机制提供了见解。
Lysine 63 (K63)-linked ubiquitination of RIG-I plays a critical role in the activation of type I interferon pathway, yet the molecular mechanism responsible for its deubiquitination is still poorly understood. Here we report that the deubiquitination enzyme ubiquitin-specific protease 3 (USP3) negatively regulates the activation of type I interferon signaling by targeting RIG-I. Knockdown of USP3 specifically enhanced K63-linked ubiquitination of RIG-I, upregulated the phosphorylation of IRF3 and augmented the production of type I interferon cytokines and antiviral immunity. We further show that there is no interaction between USP3 and RIG-I-like receptors (RLRs) in unstimulated or uninfected cells, but upon viral infection or ligand stimulation, USP3 binds to the caspase activation recruitment domain of RLRs and then cleaves polyubiquitin chains through cooperation of its zinc-finger Ub-binding domain and USP catalytic domains. Mutation analysis reveals that binding of USP3 to polyubiquitin chains on RIG-I is a prerequisite step for its cleavage of polyubiquitin chains. Our findings identify a previously unrecognized role of USP3 in RIG-I activation and provide insights into the mechanisms by which USP3 inhibits RIG-I signaling and antiviral immunity.