IFI16 directly senses viral RNA and enhances RIG-I transcription and activation to restrict influenza virus infection

Jiang, Zhimin; Wei, Fanhua; Zhang, Yuying; Wang, Tong; Gao, Weihua; Yu, Shufang; Sun, Honglei; Pu, Juan; Sun, Yipeng; Wang, Mingyang; Tong, Qi; Gao, Chengjiang; Chang, Kin-Chow; Liu, Jinhua

Abstract

The retinoic acid-inducible gene I (RIG-I) receptor senses cytoplasmic viral RNA and activates type I interferons (IFN-I) and downstream antiviral immune responses. How RIG-I binds to viral RNA and how its activation is regulated remains unclear. Here, using IFI16 knockout cells and p204-deficient mice, we demonstrate that the DNA sensor IFI16 enhances IFN-I production to inhibit influenza A virus (IAV) replication. IFI16 positively upregulates RIG-I transcription through direct binding to and recruitment of RNA polymerase II to the RIG-I promoter. IFI16 also binds to influenza viral RNA via its HINa domain and to RIG-I protein with its PYRIN domain, thus promoting IAV-induced K63-linked polyubiquitination and RIG-I activation. Our work demonstrates that IFI16 is a positive regulator of RIG-I signalling during influenza virus infection, highlighting its role in the RIG-I-like-receptor-mediated innate immune response to IAV and other RNA viruses, and suggesting its possible exploitation to modulate the antiviral response.

Citation

Jiang, Z., Wei, F., Zhang, Y., Wang, T., Gao, W., Yu, S., …Liu, J. (2021). IFI16 directly senses viral RNA and enhances RIG-I transcription and activation to restrict influenza virus infection. Nature Microbiology, 6, 932–945. https://doi.org/10.1038/s41564-021-00907-x

• Journal Article Type: Article
• Acceptance Date: Apr 6, 2021
• Online Publication Date: May 13, 2021
• Publication Date: May 13, 2021
• Deposit Date: May 18, 2021
• Publicly Available Date: Nov 14, 2021
• Journal: Nature Microbiology
• Electronic ISSN: 2058-5276
• Publisher: Nature Publishing Group
• Peer Reviewed: Peer Reviewed
• Volume: 6
• Pages: 932–945
• DOI: https://doi.org/10.1038/s41564-021-00907-x
• Keywords: Immunology; Microbiology (medical); Applied Microbiology and Biotechnology; Genetics; Cell Biology; Microbiology
• Public URL: https://nottingham-repository.worktribe.com/output/5531000
• Publisher URL: https://www.nature.com/articles/s41564-021-00907-x