STAT3 regulates antiviral immunity by suppressing excessive interferon signaling
Shasha Liu,
Siya Liu,
Ziding Yu,
Wenzhuo Zhou,
Meichun Zheng,
Rongrong Gu,
Jinxuan Hong,
Zhou Yang,
Xiaojuan Chi,
Guijie Guo,
Xinxin Li,
Na Chen,
Shile Huang,
Song Wang,
Ji-Long Chen
Affiliations
Shasha Liu
Key Laboratory of Animal Pathogen Infection and Immunology of Fujian Province, College of Animal Sciences, Fujian Agriculture and Forestry University, Fuzhou 350002, China
Siya Liu
Key Laboratory of Animal Pathogen Infection and Immunology of Fujian Province, College of Animal Sciences, Fujian Agriculture and Forestry University, Fuzhou 350002, China
Ziding Yu
Key Laboratory of Animal Pathogen Infection and Immunology of Fujian Province, College of Animal Sciences, Fujian Agriculture and Forestry University, Fuzhou 350002, China
Wenzhuo Zhou
Key Laboratory of Animal Pathogen Infection and Immunology of Fujian Province, College of Animal Sciences, Fujian Agriculture and Forestry University, Fuzhou 350002, China
Meichun Zheng
Key Laboratory of Animal Pathogen Infection and Immunology of Fujian Province, College of Animal Sciences, Fujian Agriculture and Forestry University, Fuzhou 350002, China
Rongrong Gu
Key Laboratory of Animal Pathogen Infection and Immunology of Fujian Province, College of Animal Sciences, Fujian Agriculture and Forestry University, Fuzhou 350002, China
Jinxuan Hong
Key Laboratory of Animal Pathogen Infection and Immunology of Fujian Province, College of Animal Sciences, Fujian Agriculture and Forestry University, Fuzhou 350002, China
Zhou Yang
Key Laboratory of Animal Pathogen Infection and Immunology of Fujian Province, College of Animal Sciences, Fujian Agriculture and Forestry University, Fuzhou 350002, China
Xiaojuan Chi
Key Laboratory of Animal Pathogen Infection and Immunology of Fujian Province, College of Animal Sciences, Fujian Agriculture and Forestry University, Fuzhou 350002, China
Guijie Guo
Key Laboratory of Animal Pathogen Infection and Immunology of Fujian Province, College of Animal Sciences, Fujian Agriculture and Forestry University, Fuzhou 350002, China
Xinxin Li
Key Laboratory of Animal Pathogen Infection and Immunology of Fujian Province, College of Animal Sciences, Fujian Agriculture and Forestry University, Fuzhou 350002, China
Na Chen
Key Laboratory of Animal Pathogen Infection and Immunology of Fujian Province, College of Animal Sciences, Fujian Agriculture and Forestry University, Fuzhou 350002, China
Shile Huang
Department of Biochemistry and Molecular Biology, Louisiana State University Health Sciences Center, Shreveport, LA 71130, USA
Song Wang
Key Laboratory of Animal Pathogen Infection and Immunology of Fujian Province, College of Animal Sciences, Fujian Agriculture and Forestry University, Fuzhou 350002, China
Ji-Long Chen
Key Laboratory of Animal Pathogen Infection and Immunology of Fujian Province, College of Animal Sciences, Fujian Agriculture and Forestry University, Fuzhou 350002, China; CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences (CAS), Beijing 100101, China; Corresponding author
Summary: This study identifies interleukin-6 (IL-6)-independent phosphorylation of STAT3 Y705 at the early stage of infection with several viruses, including influenza A virus (IAV). Such activation of STAT3 is dependent on the retinoic acid-induced gene I/mitochondrial antiviral-signaling protein/spleen tyrosine kinase (RIG-I/MAVS/Syk) axis and critical for antiviral immunity. We generate STAT3Y705F/+ knockin mice that display a remarkably suppressed antiviral response to IAV infection, as evidenced by impaired expression of several antiviral genes, severe lung tissue injury, and poor survival compared with wild-type animals. Mechanistically, STAT3 Y705 phosphorylation restrains IAV pathogenesis by repressing excessive production of interferons (IFNs). Blocking phosphorylation significantly augments the expression of type I and III IFNs, potentiating the virulence of IAV in mice. Importantly, knockout of IFNAR1 or IFNLR1 in STAT3Y705F/+ mice protects the animals from lung injury and reduces viral load. The results indicate that activation of STAT3 by Y705 phosphorylation is vital for establishment of effective antiviral immunity by suppressing excessive IFN signaling induced by viral infection.
