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

• DOI: 10.1038/s41564-021-00907-x
• Publication Date: 2021-05-13T16:03:15Z
• Authors: Zhimin Jiang; Fanhua Wei; Yuying Zhang; Tong Wang; Weihua Gao; Shufang Yu; Honglei Sun; Juan Pu; Yipeng Sun; Mingyang Wang; Qi Tong; Chengjiang Gao; Kin-Chow Chang; Jinhua Liu
• Keywords: Microbiology (medical); 0301 basic medicine; Immunology; Applied Microbiology and Biotechnology; Microbiology; Mice; 03 medical and health sciences; Orthomyxoviridae Infections; Genetics; Animals; Humans; Receptors, Immunologic; Promoter Regions, Genetic; Nuclear Proteins; RNA-Binding Proteins; Cell Biology; Phosphoproteins; Immunity, Innate; Up-Regulation; 3. Good health; Influenza A virus; Host-Pathogen Interactions; Interferon Type I; DEAD Box Protein 58; RNA, Viral; Protein Binding; Signal Transduction

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.