SARS coronavirus papain-like protease inhibits the type I interferon signaling pathway through interaction with the STING-TRAF3-TBK1 complex.
10.1007/s13238-014-0026-3
- Author:
Xiaojuan CHEN
1
;
Xingxing YANG
;
Yang ZHENG
;
Yudong YANG
;
Yaling XING
;
Zhongbin CHEN
Author Information
1. Division of Infection and Immunity, Department of Electromagnetic and Laser Biology, Beijing Institute of Radiation Medicine, Beijing, 100850, China.
- Publication Type:Journal Article
- MeSH:
Dimerization;
HEK293 Cells;
Humans;
I-kappa B Kinase;
metabolism;
Interferon Regulatory Factor-3;
metabolism;
Interferon Type I;
antagonists & inhibitors;
metabolism;
Membrane Proteins;
chemistry;
genetics;
metabolism;
Papain;
metabolism;
Peptide Hydrolases;
chemistry;
metabolism;
Phosphorylation;
Protein Binding;
Protein Structure, Tertiary;
Protein-Serine-Threonine Kinases;
metabolism;
SARS Virus;
enzymology;
Signal Transduction;
TNF Receptor-Associated Factor 3;
metabolism;
Ubiquitination
- From:
Protein & Cell
2014;5(5):369-381
- CountryChina
- Language:English
-
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.
