P200 family protein IFI204 negatively regulates type I interferon responses by targeting IRF7 in nucleus

Abstract

Interferon-inducible p200 family protein IFI204 was reported to be involved in DNA sensing, and subsequently induces the production of type I interferons and proinflammatory mediators. However, its function in the regulation of antiviral innate immune signaling pathway remains unclear. Here we reported a novel role of IFI204 that specifically inhibits the IRF7-mediated type I interferons response during viral infection. IFI204 and other p200 family proteins are highly expressed in mouse hepatitis coronavirus-infected bone marrow-derived dendritic cells. The abundant IFI204 could significantly interact with IRF7 in nucleus by its HIN domain and prevent the binding of IRF7 with its corresponding promoter. Moreover, other p200 family proteins that possess HIN domain could also inhibit the IRF7-mediated type I interferons. These results reveal that, besides the positive regulation function in type I interferon response at the early stage of DNA virus infection, the interferon-inducible p200 family proteins such as IFI204 could also negatively regulate the IRF7-mediated type I interferon response after RNA virus infection to avoid unnecessary host damage from hyper-inflammatory responses.

Author summary

The regulation of type I interferon signaling pathway is dynamic sequential processes and must be tightly regulated to keep balance between antiviral immune and hyper-inflammatory responses. The precise regulation mechanisms of the innate immune signaling pathway are still worth studying. Here, we found a novel role of the interferon-inducible p200 family protein IFI204 that specifically inhibits the IRF7-mediated type I interferon production by negative control of the transcriptional activity of IRF7 in the nucleus at the late stage of RNA virus infection. Previous studies showed that IFI204 is involved in DNA sensing during DNA virus infection to initiate antiviral immune responses. We demonstrate that IFI204 can inhibit IRF7-mediated activation of type I IFN responses induced by RNA virus infection, which is in contrast with its role in IRF3 activation in cGAS-STING DNA sensing pathway during DNA virus infection. Such negative regulation may help to avoid hyper-inflammatory responses induced by the over-activated IRF7-mediated type I interferons at late stage of the viral infection. Thus, the current study sheds light on the regulation roles of p200 family proteins and the accurate regulation system of type I interferons signaling pathway.