USP13 negatively regulates antiviral responses by deubiquitinating STING.
USP13 negatively regulates antiviral responses by deubiquitinating STING.
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DOI：
10.1038/ncomms15534
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发表时间：
2017-05-23
影响因子：
16.6
通讯作者：
Zhong B
中科院分区：
文献类型：
--
作者：
Sun H;Zhang Q;Jing YY;Zhang M;Wang HY;Cai Z;Liuyu T;Zhang ZD;Xiong TC;Wu Y;Zhu QY;Yao J;Shu HB;Lin D;Zhong B
STING（也称为MITA）对于宿主防御病毒至关重要，并且STING的活性受泛素化调节。然而，STING的去泛素化还没有完全理解。在这里，我们表明，泛素特异性蛋白酶13（USP 13）是一种STING相互作用蛋白，催化STING的去泛素化。在HSV-1感染或DNA配体转染后，USP 13的敲低或敲除增强了IRF 3和NF-κB的活化以及下游基因的表达。USP 13缺陷导致HSV-1复制受损。一致地，USP 13缺陷型小鼠比野生型同窝小鼠对致死性HSV-1感染更具抗性。从机制上讲，USP 13使多聚泛素链与STING解偶联，并阻止TBK 1募集到信号传导复合物，从而负调节细胞抗病毒反应。因此，我们的研究揭示了USP 13在先天性抗病毒免疫中的功能，并提供了对先天免疫调节的见解。cGAS-STING途径是一种DNA传感机制，通过诱导1型干扰素表达来响应病毒感染。在这里，作者展示了去遍在化酶USP 13阻止STING对病毒做出反应的机制。
STING (also known as MITA) is critical for host defence against viruses and the activity of STING is regulated by ubiquitination. However, the deubiquitination of STING is not fully understood. Here, we show that ubiquitin-specific protease 13 (USP13) is a STING-interacting protein that catalyses deubiquitination of STING. Knockdown or knockout of USP13 potentiates activation of IRF3 and NF-κB and expression of downstream genes after HSV-1 infection or transfection of DNA ligands. USP13 deficiency results in impaired replication of HSV-1. Consistently, USP13 deficient mice are more resistant than wild-type littermates to lethal HSV-1 infection. Mechanistically, USP13 deconjugates polyubiquitin chains from STING and prevents the recruitment of TBK1 to the signalling complex, thereby negatively regulating cellular antiviral responses. Our study thus uncovers a function of USP13 in innate antiviral immunity and provides insight into the regulation of innate immunity. The cGAS-STING pathway is a DNA sensing mechanism that enables response to viral infection by inducing type 1 interferon expression. Here the authors show a mechanism by which the deubiquitinating enzyme USP13 prevents STING from enabling response to virus.