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.

视黄酸诱导基因 I (RIG-I) 受体感知细胞质病毒 RNA，并激活 I 型干扰素 (IFN-I) 和下游抗病毒免疫反应。 RIG-I 如何与病毒 RNA 结合以及如何调节其激活仍不清楚。在这里，使用 IFI16 敲除细胞和 p204 缺陷小鼠，我们证明 DNA 传感器 IFI16 增强 IFN-I 的产生，从而抑制甲型流感病毒 (IAV) 复制。 IFI16 通过直接结合 RNA 聚合酶 II 并将其募集至RIG-I启动子，正向上调RIG-I转录。 IFI16 还通过其 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 连接的多聚泛素化和 RIG-I 激活。我们的工作表明，IFI16 是流感病毒感染期间 RIG-I 信号传导的正调节因子，强调了其在 RIG-I 样受体介导的针对 IAV 和其他 RNA 病毒的先天免疫反应中的作用，并表明其可能用于调节抗病毒反应。