Cell Res：钟波研究组在抗病毒天然免疫分子机制新进展
2016年11月1日，武汉大学生命科学学院钟波教授作为通讯作者在国际权威期刊Cell Research (IF：14.8)上在线发表题为“USP18 recruits USP20 to promote innate antiviral response through deubiquitinating STING/MITA”(USP18通过招募USP20去泛素化STING/MITA促进天然免疫应答)的学术论文（论文链接：http://www.nature.com/cr/journal/vaop/ncurrent/full/cr2016125a.html）。
该文阐述了USP18通过募集USP20去泛素化STING/MITA调控天然免疫应答的过程。我院2016级博士研究生张满和2015级硕士研究生张梦昕为该论文的并列第一作者。
天然免疫是保护机体抵御病原微生物的入侵的第一道生理防线。其中MITA（也称STING）介导的信号通路在机体抗DNA病毒天然免疫应答的过程中扮演着重要角色，其功能受到泛素化和去泛素化修饰的严格调控。该研究小组发现USP18通过募集USP20通过去MITA的K48连接的泛素化修饰，进而促进宿主抗DNA病毒天然免疫应答，这一过程不依赖于USP18的酶活性而依赖于USP20的酶活性。在USP18敲除和USP20敲低的细胞中，MITA的K48连接泛素化修饰增强，促进MITA通过泛素蛋白酶体途径降解，从而抑制了DNA病毒介导的IRF3和NF-κB的激活以及干扰素和炎症基因的表达。USP18敲除的小鼠对于DNA病毒HSV-1更加易感，小鼠体内的病毒复制增强，暗示着USP18在调控抗DNA病毒免疫应答过程中的关键作用，开启了泛素和去泛素调控对于天然免疫应答的新视野。
该项研究得到国家自然科学基金委面上项目、优秀青年基金、国家重大基础研究计划（973）、教育部优秀博士论文获得者基金、中组部青年千人计划项目等项目的支持。
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来源：武汉大学生命科学学院
USP18 recruits USP20 to promote innate antiviral response through deubiquitinating STING/MITA
Man Zhang1,*, Meng-Xin Zhang1,*, Qiang Zhang1, Gao-Feng Zhu1, Lei Yuan1, Dong-Er Zhang4, Qiyun Zhu3, Jing Yao1, Hong-Bing Shu2 and Bo Zhong1,2
STING (also known as MITA) mediates the innate antiviral signaling and ubiquitination of STING is key to its function. However, the deubiquitination process of STING is unclear. Here we report that USP18 recruits USP20 to deconjugate K48-linked ubiquitination chains from STING and promotes the stability of STING and the expression of type I IFNs and proinflammatory cytokines after DNA virus infection. USP18 deficiency or knockdown of USP20 resulted in enhanced K48-linked ubiquitination and accelerated degradation of STING, and impaired activation of IRF3 and NF-κB as well as induction of downstream genes after infection with DNA virus HSV-1 or transfection of various DNA ligands. In addition, Usp18−/− mice were more susceptible to HSV-1 infection compared with the wild-type littermates. USP18 did not deubiquitinate STING in vitro but facilitated USP20 to catalyze deubiquitination of STING in a manner independent of the enzymatic activity of USP18. In addition, reconstitution of STING into Usp18−/− MEFs restored HSV-1-induced expression of downstream genes and cellular antiviral responses. Our findings thus uncover previously uncharacterized roles of USP18 and USP20 in mediating virus-triggered signaling and contribute to the understanding of the complicated regulatory system of the innate antiviral responses.
http://www.nature.com/cr/journal/vaop/ncurrent/full/cr2016125a.html
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