Roles of Emerging RNA-Binding Activity of cGAS in Innate Antiviral Response.

Yuying Ma,Ji Xiao,Xiaowei Song,Zhe Ren,Yifei Wang,Yiliang Wang,Xiaohui Wang,Hanlin Shuai,Weisheng Luo

doi:10.3389/fimmu.2021.741599

Abstract

cGAS, a DNA sensor in mammalian cells, catalyzes the generation of 2’-3’-cyclic AMP-GMP (cGAMP) once activated by the binding of free DNA. cGAMP can bind to STING, activating downstream TBK1-IRF-3 signaling to initiate the expression of type I interferons. Although cGAS has been considered a traditional DNA-binding protein, several lines of evidence suggest that cGAS is a potential RNA-binding protein (RBP), which is mainly supported by its interactions with RNAs, RBP partners, RNA/cGAS-phase-separations as well as its structural similarity with the dsRNA recognition receptor 2’-5’ oligoadenylate synthase. Moreover, two influential studies reported that the cGAS-like receptors (cGLRs) of fly Drosophila melanogaster sense RNA and control 3′-2′-cGAMP signaling. In this review, we summarize and discuss in depth recent studies that identified or implied cGAS as an RBP. We also comprehensively summarized current experimental methods and computational tools that can identify or predict RNAs that bind to cGAS. Based on these discussions, we appeal that the RNA-binding activity of cGAS cannot be ignored in the cGAS-mediated innate antiviral response. It will be important to identify RNAs that can bind and regulate the activity of cGAS in cells with or without virus infection. Our review provides novel insight into the regulation of cGAS by its RNA-binding activity and extends beyond its DNA-binding activity. Our review would be significant for understanding the precise modulation of cGAS activity, providing the foundation for the future development of drugs against cGAS-triggering autoimmune diseases such as Aicardi-Gourtières syndrome.

Highlights

As highlighted by the current COVID-19 pandemic, viral infection poses a great threat to human health and economics [1]
We highlighted the RNA-binding activity of cyclic GMP-AMP synthase (cGAS) based on the RNA interactors of cGAS, the numerous RNA-binding protein (RBP) partners of cGAS, and its structural similarity with 2′-5′-OAS
We elucidated and discussed current experimental methods and computational tools that can be used for exploring and calculating cGAS-RNA interactions. These clues indicated that the RNA-binding activity of cGAS may play an important role in the innate antiviral response, which needs to be further confirmed in the future

Summary

INTRODUCTION

As highlighted by the current COVID-19 pandemic, viral infection poses a great threat to human health and economics [1]. CGAS can recognize synthetic RNA : DNA hybrids and activate downstream STING-TBK1-IRF-3 signaling to initiate the expression of I-IFNs in MAVS-knockout THP-1 cells (Figure 2C) [80]. A recent study showed that the disruption of the ribosome-associated protein quality control (RQC) pathway under stressful conditions such as viral infection, which detects and resolves ribosome collision during translation, results in cGAS-dependent ISG expression and causes relocalization of cGAS from the nucleus to the cytosol [103]. We comprehensively summarized the current experimental methods (Table 3) and computational tools (Table 4) for studying RNA-protein interactions as well as their respective advantages and disadvantages These methods would be beneficial for us to identify RNAs that bind to cGAS and reveal the RNA-binding activity of cGAS and its regulatory function in the antiviral immune response. On the basis of these principles, there are methods such as RPI-Pred and PRIPU that further introduced statistical and machine learning algorithms, including vector machines, in the prediction of RNA-protein interactions [141, 142] (Table 4)

CONCLUSIONS AND FUTURE PERSPECTIVES

Methods