Broad and diverse mechanisms used by deubiquitinase family members in regulating the type I interferon signaling pathway during antiviral responses.
Broad and diverse mechanisms used by deubiquitinase family members in regulating the type I interferon signaling pathway during antiviral responses.
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去泛素酶家族成员在抗病毒反应期间调节 I 型干扰素信号通路所使用的广泛而多样的机制
DOI：
10.1126/sciadv.aar2824
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发表时间：
2018-05
期刊：
影响因子：
13.6
通讯作者：
Cui J
中科院分区：
文献类型：
--
作者：
Liu Q;Wu Y;Qin Y;Hu J;Xie W;Qin FX;Cui J
去泛素酶家族蛋白通过动态和多样的机制广泛参与调节抗病毒反应。I型干扰素产生的先天免疫反应对于宿主抵御病毒感染是必不可少的，但需要严格控制以避免免疫病理。我们通过CRISPR/Cas9(簇状规则间隔短回文重复序列/CRISPR相关蛋白9)敲除和过度表达进行了系统的功能筛选，以研究去泛素酶(DUB)家族在调节抗病毒免疫中的作用。我们证明了很大一部分DUBS的表达经历了复杂的时间变化，表明了反馈调节的动态程序。此外，我们还确定了以前未知的DUB子集，包括USP5、USP14、USP22、USP48、USP52、COPS5和BRCC3，在不同水平上抑制抗病毒免疫。我们探索了一种意想不到的机制，即多个DUB，如USP5和USP22，与E3连接酶或DUB形成不同的信号体，以改变底物的泛素化状态，而不是通过其蛋白酶活性直接断裂底物上的泛素链。总之，我们的研究揭示了DuB家族蛋白在调节抗病毒反应中的广泛和动态参与的全景。
Deubiquitinase family proteins are broadly involved in modulating antiviral response through dynamic and diverse mechanisms. The innate immune response conferred by type I interferons is essential for host defense against viral infection but needs to be tightly controlled to avoid immunopathology. We performed a systematic functional screening by CRISPR/Cas9 (clustered regularly interspaced short palindromic repeats/CRISPR-associated protein 9) knockout and overexpression to investigate the roles of the deubiquitinating enzyme (DUB) family in regulating antiviral immunity. We demonstrated that the expression of a large fraction of DUBs underwent complex temporal alteration, suggesting a dynamic program of feedback regulation. Moreover, we identified previously unrecognized roles of a subset of DUBs, including USP5, USP14, USP22, USP48, USP52, COPS5, and BRCC3, in inhibiting antiviral immunity at various levels. We explored an unexpected mechanism where multiple DUBs, such as USP5 and USP22, form diverse signalosomes with E3 ligases or DUBs to alter the substrates’ ubiquitination state instead of directly cleaving the ubiquitin chains on substrates via their protease activity. Altogether, our study has revealed a panoramic view of the broad and dynamic involvement of DUB family proteins in regulating antiviral responses.
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