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

  • Nat Microbiol. 2021 Jul;6(7):932-945. doi: 10.1038/s41564-021-00907-x.
Zhimin Jiang   #  1 ,  Fanhua Wei   #  2 ,  Yuying Zhang  3 ,  Tong Wang  1 ,  Weihua Gao  1 ,  Shufang Yu  4 ,  Honglei Sun  1 ,  Juan Pu  1 ,  Yipeng Sun  1 ,  Mingyang Wang  1 ,  Qi Tong  1 ,  Chengjiang Gao  5 ,  Kin-Chow Chang  6 ,  Jinhua Liu  7
Affiliations
  • 1. Key Laboratory of Animal Epidemiology and Zoonosis, Ministry of Agriculture, College of Veterinary Medicine and State Key Laboratory of Agrobiotechnology, China Agricultural University, Beijing, China.
  • 2. College of Agriculture, Ningxia University, Yinchuan, China. [email protected].
  • 3. School of Biological Science and Technology, University of Jinan, Jinan, China.
  • 4. College of Agriculture, Ningxia University, Yinchuan, China.
  • 5. Key Laboratory of Infection and Immunity of Shandong Province and Department of Immunology, School of Biomedical Sciences, Shandong University, Jinan, China.
  • 6. School of Veterinary Medicine and Science, University of Nottingham, Sutton Bonington Campus, Sutton Bonington, UK.
  • 7. Key Laboratory of Animal Epidemiology and Zoonosis, Ministry of Agriculture, College of Veterinary Medicine and State Key Laboratory of Agrobiotechnology, China Agricultural University, Beijing, China. [email protected].
  • # Contributed equally.
PMID: 33986530 DOI: 10.1038/s41564-021-00907-x
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.

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