title: SARS coronavirus papain-like protease inhibits the type I interferon signaling pathway through interaction with the STING-TRAF3-TBK1 complex.
abstract: SARS coronavirus (SARS-CoV) develops an antagonistic mechanism by which to evade the antiviral activities of interferon (IFN). Previous studies suggested that SARS-CoV papain-like protease (PLpro) inhibits activation 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 efficiently inhibits activation of the IRF3 pathway. We found that expression of the membrane-anchored PLpro domain (PLpro-TM) from SARS-CoV inhibits STING/TBK1/IKKε-mediated activation of type I IFNs and disrupts the phosphorylation and dimerization of IRF3, which are activated by STING and TBK1. Meanwhile, we showed that PLpro-TM physically interacts with TRAF3, TBK1, IKKε, STING, and IRF3, the key components that assemble the STING-TRAF3-TBK1 complex for activation of IFN expression. However, the interaction between the components in STING-TRAF3-TBK1 complex is disrupted 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 with STING-TRAF3-TBK1 complex, yielding a SARS-CoV countermeasure against host innate immunity.
authors.affiliation: Division of Infection and Immunity, Department of Electromagnetic and Laser Biology, Beijing Institute of Radiation Medicine, Beijing, 100850, China.
authors.forename: Xiaojuan
authors.initials: X
authors.lastname: Chen
authors.forename: Xingxing
authors.initials: X
authors.lastname: Yang
authors.forename: Yang
authors.initials: Y
authors.lastname: Zheng
authors.forename: Yudong
authors.initials: Y
authors.lastname: Yang
authors.forename: Yaling
authors.initials: Y
authors.lastname: Xing
authors.forename: Zhongbin
authors.initials: Z
authors.lastname: Chen
mesh_terms: D019281:Dimerization; D057809:HEK293 Cells; D006801:Humans; D051550:I-kappa B Kinase / Q000378:metabolism; D050838:Interferon Regulatory Factor-3 / Q000378:metabolism; D007370:Interferon Type I / Q000037:antagonists & inhibitors / Q000378:metabolism*; D008565:Membrane Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D010206:Papain / Q000378:metabolism; D010447:Peptide Hydrolases / Q000737:chemistry / Q000378:metabolism*; D010766:Phosphorylation; D011485:Protein Binding; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D017434:Protein Structure, Tertiary; D045473:Severe acute respiratory syndrome-related coronavirus / Q000201:enzymology*; D015398:Signal Transduction; D048008:TNF Receptor-Associated Factor 3 / Q000378:metabolism*; D054875:Ubiquitination; D000099197:STING Protein
chemical_list: D051550:I-kappa B Kinase; D050838:Interferon Regulatory Factor-3; D007370:Interferon Type I; D008565:Membrane Proteins; D010206:Papain; D010447:Peptide Hydrolases; D017346:Protein Serine-Threonine Kinases; D048008:TNF Receptor-Associated Factor 3; C532857:STING1 protein, human; D000099197:STING Protein; C090656:TRAF3 protein, human; C403191:TBK1 protein, human