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.
College of Agriculture, Ningxia University, Yinchuan, China.
Nat Microbiol. 2021 Jul;6(7):932-945. doi: 10.1038/s41564-021-00907-x. Epub 2021 May 13.
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.
维甲酸诱导基因 I（RIG-I）受体感知细胞质中的病毒 RNA，并激活 I 型干扰素（IFN-I）和下游抗病毒免疫反应。RIG-I 如何结合病毒 RNA，以及其激活如何被调节，目前仍不清楚。在这里，我们使用 IFI16 敲除细胞和 p204 缺陷型小鼠，证明 DNA 传感器 IFI16 通过直接结合和募集 RNA 聚合酶 II 到 RIG-I 启动子，从而增强 IFN-I 的产生，以抑制甲型流感病毒（IAV）的复制。IFI16 通过其 HINa 结构域与流感病毒 RNA 结合，并通过其 PYRIN 结构域与 RIG-I 蛋白结合，从而促进 IAV 诱导的 K63 连接多聚泛素化和 RIG-I 激活。我们的工作表明，IFI16 是流感病毒感染期间 RIG-I 信号的正向调节剂，突出了它在 RIG-I 样受体介导的对 IAV 和其他 RNA 病毒的先天免疫反应中的作用，并表明其可能被利用来调节抗病毒反应。
