Critical role of Syk-dependent STAT1 activation in innate antiviral immunity

Shasha Liu; Yuan Liao; Biao Chen; Yuhai Chen; Ziding Yu; Haitao Wei; Lianfeng Zhang; Shile Huang; Paul B Rothman; George Fu Gao; Ji-Long Chen

doi:10.1016/j.celrep.2020.108627

Critical role of Syk-dependent STAT1 activation in innate antiviral immunity

Cell Rep. 2021 Jan 19;34(3):108627. doi: 10.1016/j.celrep.2020.108627.

Authors

Shasha Liu¹, Yuan Liao², Biao Chen¹, Yuhai Chen³, Ziding Yu², Haitao Wei³, Lianfeng Zhang⁴, Shile Huang⁵, Paul B Rothman⁶, George Fu Gao³, Ji-Long Chen⁷

Affiliations

¹ CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences (CAS), Beijing 100101, China; University of Chinese Academy of Sciences, Beijing 100049, China.
² Key Laboratory of Fujian-Taiwan Animal Pathogen Biology, College of Animal Sciences, Fujian Agriculture and Forestry University, Fuzhou 350002, China.
³ CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences (CAS), Beijing 100101, China.
⁴ Key Laboratory of Human Disease Comparative Medicine, Ministry of Health, Institute of Laboratory Animal Science, Chinese Academy of Medical Sciences & Comparative Medical Center, Peking Union Medical College, Beijing 100021, China.
⁵ Department of Biochemistry and Molecular Biology, Louisiana State University Health Sciences Center, Shreveport, LA 71130, USA.
⁶ Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
⁷ CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences (CAS), Beijing 100101, China; Key Laboratory of Fujian-Taiwan Animal Pathogen Biology, College of Animal Sciences, Fujian Agriculture and Forestry University, Fuzhou 350002, China. Electronic address: chenjl@im.ac.cn.

PMID: 33472080
DOI: 10.1016/j.celrep.2020.108627

Abstract

The JAK/STAT1 pathway is generally activated by cytokines, providing essential antiviral defense. Here, we identify that STAT1 activation is independent of cytokines and JAKs at the early infection stage of some viruses, including influenza A virus (IAV). Instead, STAT1 is activated mainly through spleen tyrosine kinase (Syk) downstream of retinoic acid-inducible gene-I/mitochondrial antiviral-signaling protein (RIG-I/MAVS) signaling. Syk deletion profoundly impairs immediate innate immunity, as evidenced by the finding that Syk deletion attenuates tyrosine phosphorylation of STAT1 and reduces the expressions of interferon-stimulated genes (ISGs) in vitro and in vivo. The antiviral response to IAV infection is also significantly suppressed in the STAT1^Y701F knockin mice. The results demonstrate that STAT1 activation is dependent on Syk rather than the cytokine-activated JAK signaling at the early stage of viral infection, which is critical for initial antiviral immunity. Our finding provides insights into the complicated mechanisms underlying host immune responses to viral infection.

Keywords: MAVS; RIG-I; STAT1; Syk; cytokine; influenza virus; innate immunity.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Chlorocebus aethiops
Female
HEK293 Cells
Humans
Immunity, Innate / immunology*
Mice
Mice, Inbred C57BL
NIH 3T3 Cells
Phosphorylation
STAT1 Transcription Factor / immunology*
Syk Kinase / immunology*
Syk Kinase / metabolism
Vero Cells
Virus Diseases / immunology*

Substances

STAT1 Transcription Factor
STAT1 protein, human
Syk Kinase