2. Academic Validation
  3. Activation of the cGAS-STING-IRF3 Axis by Type I and II Interferons Contributes to Host Defense

Activation of the cGAS-STING-IRF3 Axis by Type I and II Interferons Contributes to Host Defense

  • Adv Sci (Weinh). 2024 Jul 14:e2308890. doi: 10.1002/advs.202308890.
Zhen Tong 1 2,  Jia-Peng Zou 1 2,  Su-Yun Wang 1,  Wei-Wei Luo 1 2 3,  Yan-Yi Wang 1 2
Affiliations

Affiliations

  • 1 Key Laboratory of Virology and Biosafety, Wuhan Institute of Virology, Center for Biosafety Mega-Science, Chinese Academy of Sciences, Wuhan, 430071, China.
  • 2 University of Chinese Academy of Sciences, Bejing, 100049, China.
  • 3 Hubei Jiangxia Laboratory, Wuhan, Hubei, 430200, China.
PMID: 39004913 DOI: 10.1002/advs.202308890
Abstract

Interferons (IFNs) activate JAK-STAT pathways to induce downstream effector genes for host defense against invaded pathogens and tumors. Here both type I (β) and II (γ) IFNs are shown that can activate the transcription factor IRF3 in parallel with STAT1. IRF3-deficiency impairs transcription of a subset of downstream effector genes induced by IFN-β and IFN-γ. Mechanistically, IFN-induced activation of IRF3 is dependent on the cGAS-STING-TBK1 axis. Both IFN-β and IFN-γ cause mitochondrial DNA release into the cytosol. In addition, IFNs induce JAK1-mediated tyrosine phosphorylation of cGAS at Y214/Y215, which is essential for its DNA binding activity and signaling. Furthermore, deficiency of cGAS, STING, or IRF3 impairs IFN-β- or IFN-γ-mediated Antiviral and antitumor activities. The findings reveal a novel IRF3 activation pathway parallel with the canonical STAT1/2 activation pathways triggered by IFNs and provide an explanation for the pleiotropic roles of the cGAS-STING-IRF3 axis in host defense.

Keywords

JAK‐STATs; antitumor; antiviral responses; cGAS‐STING‐IRF3; interferon; phosphorylation.

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