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

doi:10.1016/j.celrep.2023.112806

STAT3 regulates antiviral immunity by suppressing excessive interferon signaling

Cell Rep. 2023 Jul 25;42(7):112806. doi: 10.1016/j.celrep.2023.112806. Epub 2023 Jul 11.

Authors

Shasha Liu¹, Siya Liu¹, Ziding Yu¹, Wenzhuo Zhou¹, Meichun Zheng¹, Rongrong Gu¹, Jinxuan Hong¹, Zhou Yang¹, Xiaojuan Chi¹, Guijie Guo¹, Xinxin Li¹, Na Chen¹, Shile Huang², Song Wang¹, Ji-Long Chen³

Affiliations

¹ Key Laboratory of Animal Pathogen Infection and Immunology of Fujian Province, College of Animal Sciences, Fujian Agriculture and Forestry University, Fuzhou 350002, China.
² Department of Biochemistry and Molecular Biology, Louisiana State University Health Sciences Center, Shreveport, LA 71130, USA.
³ 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. Electronic address: chenjilong@fafu.edu.cn.

PMID: 37440406
DOI: 10.1016/j.celrep.2023.112806

Abstract

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 STAT3^Y705F/+ 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 STAT3^Y705F/+ 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.

Keywords: CP: Immunology; IL-6; MAVS; RIG-I; STAT3; influenza A virus; innate immunity; interferon.

Publication types

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

MeSH terms

Animals
Antiviral Agents
Immunity, Innate
Influenza A virus*
Interferons
Mice
Orthomyxoviridae Infections* / immunology
Receptors, Interferon
STAT3 Transcription Factor* / immunology
Signal Transduction

Substances

Antiviral Agents
IFNLR1 protein, mouse
Interferons
Receptors, Interferon
Stat3 protein, mouse
STAT3 Transcription Factor