SARS coronavirus papain-like protease inhibits the type I interferon signaling pathway through interaction with the STING-TRAF3- TBK1 complex

作     者：Xiaojuan Chen Xingxing Yang Yang Zheng Yudong Yang Yaling Xing Zhongbin Chen 

作者机构：Division of Infection and Immunity Department of Electromagnetic and Laser Biology Beijing Institute of Radiation Medicine_ Beijing 100850 China Anhui Medical University Hefei 230032 China 

出 版 物：《Protein & Cell》 (蛋白质与细胞（英文版）)

年 卷 期：2014年第5卷第5期

页      面：369-381页

核心收录：

学科分类：0710[理学-生物学] 0831[工学-生物医学工程（可授工学、理学、医学学位）] 1007[医学-药学(可授医学、理学学位)] 071010[理学-生物化学与分子生物学] 1002[医学-临床医学] 07[理学] 1001[医学-基础医学(可授医学、理学学位)] 100103[医学-病原生物学] 0703[理学-化学] 0836[工学-生物工程] 10[医学] 

基　　金：supported by grants received from the National Natural Science Foundation of China to Z.C. supported by grants received from the National Natural Science Foundation of China to Y.X. 

主　　题：SARS coronavirus papain-like protease,interferon deubiquitinase STING-TRAF3-TBK1 complex 

摘      要：SARS coronavirus （SARS-CoV） develops an antagonis- tic mechanism by which to evade the antiviral activities of interferon （IFN）. Previous studies suggested that SARS-CoV papain-like protease （PLpro） inhibits activa- tion of the IRF3 pathway, which would normally elicit a robust IFN response, but the mechanism（s） used by SARS PLpro to inhibit activation of the IRF3 pathway is not fully known. In this study, we uncovered a novel mechanism that may explain how SARS PLpro effi- ciently inhibits activation of the IRF3 pathway. We found that expression of the membrane-anchored PLpro domain （PLpro-TM） from SARS-CoV inhibits STING/ TBKl/IKKE-mediated activation of type I IFNs and dis- rupts the phosphorylation and dimerization of IRF3, which are activated by STING and TBKI. Meanwhile, we showed that PLpro-TM physically interacts with TRAF3, TBK1, IKK~, STING, and IRF3, the key components that assemble the STING-TRAF3-TBK1 complex for activa- tion of IFN expression. However, the interaction between the components in STING-TRAF3-TBK1 complex is dis- rupted by PLpro-TM. Furthermore, SARS PLpro-TM reduces the levels of ubiquitinated forms of RIG-I, STING, TRAF3, TBK1, and IRF3 in the STING-TRAF3- TBK1 complex. These results collectively point to a new mechanism used by SARS-CoV through which PLpro negatively regulates IRF3 activation by interaction withSTING-TRAF3-TBK1 complex, yielding a SARS-CoV countermeasure against host innate immunity.