Fip200 Is Essential For Rig-I-Mediated Innate Immune Signaling

Abstract Retinoic acid-inducible gene I (RIG-I) is a cytosolic sensor for recognition of viral double-stranded RNA (dsRNA) and 5′ triphosphate RNA, which induces a robust production of type I interferon (IFN). Following RNA recognition, the caspase activation and recruitment domain (CARD) of RIG-I is released from the repressor domain and subsequently oligomerized to activate downstream signal cascades. Although these sequential steps for RIG-I activation are well established; however, the regulatory mechanism is not well elucidated. In this study, we found that the FAK family kinase-interacting protein of 200 kDa (FIP200) interacted with the CARD domain of RIG-I. Ectopic expression of FIP200 activated RIG-I. By contrast, knockout of FIP200 impaired RIG-I signaling, but not other innate immune signaling pathways, in fibroblasts and macrophages. In vivo study showed FIP200 knockout mice were more susceptible to VSV, but not HSV-1, infection due to the reduced innate immune responses, including type I IFN. Mechanistic analyses found that FIP200 promoted the release of the CARD by competing with the repressor domain of RIG-I. Furthermore, FIP200 formed dimers via its C-terminal tail, which facilitated RIG-I oligomerization and subsequent activation. Taken together, our study defines FIP200 as a new innate immune signaling molecule and facilities RIG-I activation.