Viral suppression of innate immunity via spatial isolation of TBK1/IKKε from mitochondrial antiviral platform.
For antiviral signaling mediated by retinoic acid-inducible gene I (RIG-I)-like receptors (RLRs), the recruitment of cytosolic RLRs and downstream molecules (such as TBK1 and IKKε) to mitochondrial platform is a central event that facilitates the establishment of host antiviral state. Here, we present an example of viral targeting for immune evasion through spatial isolation of TBK1/IKKε from mitochondrial antiviral platform, which was employed by severe fever with thrombocytopenia syndrome virus (SFTSV), a deadly bunyavirus emerging recently. We showed that SFTSV nonstructural protein NSs functions as the interferon (IFN) antagonist, mainly via suppressing TBK1/IKKε-IRF3 signaling. NSs mediates the formation of cytoplasmic inclusion bodies (IBs), and the blockage of IB formation impairs IFN-inhibiting activity of NSs. We next demonstrate that IBs are utilized to compartmentalize TBK1/IKKε. The compartmentalization results in spatial isolation of the kinases from mitochondria, and deprived TBK1/IKKε may participate in antiviral complex assembly, leading to the blockage of IFN induction. This study proposes a new role of viral IBs as virus-built 'jail' for imprisoning cellular factors and presents a novel and likely common mechanism of viral immune evasion through spatial isolation of critical signaling molecules from the mitochondrial antiviral platform.
State Key Laboratory of Virology, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan 430071, China.
Yun-Jia
YJ
Ning
State Key Laboratory of Virology, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan 430071, China.
Manli
M
Wang
State Key Laboratory of Virology, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan 430071, China.
Maping
M
Deng
State Key Laboratory of Virology, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan 430071, China.
Shu
S
Shen
State Key Laboratory of Pathogen and Biosecurity, Beijing Institute of Microbiology and Epidemiology, Beijing 100071, China.
Wei
W
Liu
State Key Laboratory of Pathogen and Biosecurity, Beijing Institute of Microbiology and Epidemiology, Beijing 100071, China.
Wu-Chun
WC
Cao
State Key Laboratory of Virology, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan 430071, China.
Fei
F
Deng
State Key Laboratory of Virology, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan 430071, China.
Yan-Yi
YY
Wang
State Key Laboratory of Virology, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan 430071, China h.wang@wh.iov.cn huzh@wh.iov.cn.
Zhihong
Z
Hu
State Key Laboratory of Virology, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan 430071, China h.wang@wh.iov.cn huzh@wh.iov.cn.
Hualin
H
Wang
D000998:Antiviral Agents / Q000494:pharmacology; D015153:Blotting, Western; D005455:Fluorescent Antibody Technique; D006801:Humans; D051550:I-kappa B Kinase / Q000235:genetics / Q000378:metabolism*; D007113:Immunity, Innate / Q000276:immunology*; D047468:Immunoprecipitation; D007181:Inclusion Bodies, Viral / Q000276:immunology; D050838:Interferon Regulatory Factor-3 / Q000235:genetics / Q000378:metabolism; D016899:Interferon-beta / Q000235:genetics / Q000378:metabolism; D008928:Mitochondria / Q000276:immunology* / Q000378:metabolism / Q000821:virology; D010217:Phlebotomus Fever / Q000276:immunology / Q000378:metabolism* / Q000821:virology; D016856:Phlebovirus / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D011401:Promoter Regions, Genetic; D060066:Protein Interaction Maps; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D020218:Response Elements / Q000235:genetics; D015398:Signal Transduction; D017361:Viral Nonstructural Proteins / Q000235:genetics / Q000276:immunology* / Q000378:metabolism
D000998:Antiviral Agents; C494232:IRF3 protein, human; D050838:Interferon Regulatory Factor-3; D017361:Viral Nonstructural Proteins; D016899:Interferon-beta; D017346:Protein Serine-Threonine Kinases; C403191:TBK1 protein, human; D051550:I-kappa B Kinase
TBK1/IKKε; immune evasion; inclusion bodies; innate immunity; severe fever with thrombocytopenia syndrome virus; spatial isolation