FIP200 restricts RNA virus infection by facilitating RIG-I activation

Lingyan Wang,Lin Liu,Chaoqun Huang,Yiwen Sun,Jun-Lin Guan,Girish Patil,Fang Hua,Jerry Ritchey,Wenzhuo Hao,Clinton Jones,Yakun Wu,Kun Song,Shitao Li

doi:10.1038/s42003-021-02450-1

Abstract

Retinoic acid-inducible gene I (RIG-I) senses viral RNA and instigates an innate immune signaling cascade to induce type I interferon expression. Currently, the regulatory mechanisms controlling RIG-I activation remain to be fully elucidated. Here we show that the FAK family kinase-interacting protein of 200 kDa (FIP200) facilitates RIG-I activation. FIP200 deficiency impaired RIG-I signaling and increased host susceptibility to RNA virus infection. In vivo studies further demonstrated FIP200 knockout mice were more susceptible to RNA virus infection due to the reduced innate immune response. Mechanistic studies revealed that FIP200 competed with the helicase domain of RIG-I for interaction with the two tandem caspase activation and recruitment domains (2CARD), thereby facilitating the release of 2CARD from the suppression status. Furthermore, FIP200 formed a dimer and facilitated 2CARD oligomerization, thereby promoting RIG-I activation. Taken together, our study defines FIP200 as an innate immune signaling molecule that positively regulates RIG-I activation.

Highlights

Retinoic acid-inducible gene I (RIG-I) senses viral RNA and instigates an innate immune signaling cascade to induce type I interferon expression
Using a stringent statistical SAINT score cutoff of 0.89 (P < 0.01), we identified twelve high-confidence candidate interacting proteins, including two well-known interactors, ATG13 and ATG10120–22 (Supplementary Fig. 1b; Supplementary Data 1), which substantiates the high quality of our family kinase-interacting protein of 200 kDa (FIP200) protein interaction network
We further examined the effect of FIP200 deficiency on another RNA virus, human coronavirus (HCoV) OC43, which is not inhibited by autophagy[29]

Summary

Introduction

Retinoic acid-inducible gene I (RIG-I) senses viral RNA and instigates an innate immune signaling cascade to induce type I interferon expression. FIP200 deficiency impaired RIG-I signaling and increased host susceptibility to RNA virus infection. Mechanistic studies revealed that FIP200 competed with the helicase domain of RIG-I for interaction with the two tandem caspase activation and recruitment domains (2CARD), thereby facilitating the release of 2CARD from the suppression status. In the absence of RNA ligand, RIG-I is auto-repressed because the 2CARD is prevented from forming the active conformation due to the binding of the helicase domain. Recent studies showed that RIG-I is constitutively phosphorylated at the 2CARD and CTD domains, which further prevents RIG-I from activation[4,5,6]. We show that FIP200 is essential for RIG-I activation and host defense to RNA virus infection. Deficiency of FIP200 impaired dsRNA-induced type I IFN expression and increased host susceptibility to vesicular stomatitis virus (VSV) and human coronavirus (HCoV) OC43 infection.

Methods

Results

Conclusion