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.
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.
