\u03b2-arrestin 2 as an activator of cGAS-STING signaling and target of viral immune evasion

Yihua Zhang,Feng Huang,Quanming Zou,Jing Liu,Manman Li,Liuyan Li,Chao Fang,Gui Qian,Yu Wang,Zijuan Chen,Daqiao Guo,Dapeng Yan,Yiwei Chu

doi:10.1038/s41467-020-19849-9

Abstract

Virus infection may induce excessive interferon (IFN) responses that can lead to host tissue injury or even death. β-arrestin 2 regulates multiple cellular events through the G protein-coupled receptor (GPCR) signaling pathways. Here we demonstrate that β-arrestin 2 also promotes virus-induced production of IFN-β and clearance of viruses in macrophages. β-arrestin 2 interacts with cyclic GMP-AMP synthase (cGAS) and increases the binding of dsDNA to cGAS to enhance cyclic GMP-AMP (cGAMP) production and the downstream stimulator of interferon genes (STING) and innate immune responses. Mechanistically, deacetylation of β-arrestin 2 at Lys171 facilitates the activation of the cGAS–STING signaling and the production of IFN-β. In vitro, viral infection induces the degradation of β-arrestin 2 to facilitate immune evasion, while a β-blocker, carvedilol, rescues β-arrestin 2 expression to maintain the antiviral immune response. Our results thus identify a viral immune-evasion pathway via the degradation of β-arrestin 2, and also hint that carvedilol, approved for treating heart failure, can potentially be repurposed as an antiviral drug candidate.

Highlights

Virus infection may induce excessive interferon (IFN) responses that can lead to host tissue injury or even death. β-arrestin 2 regulates multiple cellular events through the G proteincoupled receptor (GPCR) signaling pathways
CGAS acts as a cytosolic DNA sensor that initiates the stimulator of interferon genes (STING)–TANK-binding kinase-1 (TBK1)–IFN regulatory factor 3 (IRF3)-type I IFN signaling cascade, the location of cyclic GMP-AMP synthase (cGAS) largely influences its functions. cGAS diffuses throughout the cytosol to search its DNA ligand and localizes at the plasma membrane and in the nucleus, which is associated with distinguishing self- and viral DNA, DNA damage, and tumor growth[26,27,28]
We observed that βarrestin 2 protein level was decreased (Fig. 1a and Supplementary Fig. 1a), whereas the abundance of mRNA expression of βarrestin 2 was not affected by the virus infection (Fig. 1b), indicating that β-arrestin 2 is probably degraded by viruses in a posttranslational manner

Summary

Introduction

Virus infection may induce excessive interferon (IFN) responses that can lead to host tissue injury or even death. β-arrestin 2 regulates multiple cellular events through the G proteincoupled receptor (GPCR) signaling pathways. We demonstrate that β-arrestin 2 promotes virus-induced production of IFN-β and clearance of viruses in macrophages. Βarrestin 2 interacts with cyclic GMP-AMP synthase (cGAS) and increases the binding of dsDNA to cGAS to enhance cyclic GMP-AMP (cGAMP) production and the downstream stimulator of interferon genes (STING) and innate immune responses. Despite the diversity of viruses, host immune cells are able to evolve various powerful PRRs and innate immune signaling pathways to detect the PAMPs. Toll-like receptors (TLRs), retinoic acid-inducible gene I (RIG-I)-like receptors (RLRs), and DNA sensors recognize viral nucleic acids and initiate downstream signal transduction, resulting in the induction of type I interferons (IFNs) and other proinflammatory cytokines to protect the host against virus invasion[5,6]. STING recruits and activates TBK1 and IRF3, and induces the production of type I IFNs and proinflammatory cytokines. Carvedilol was found to increase β-arrestin 2 expression and the recruitment of β-arrestin 2 to the β2AR43,44

Methods

Results

Conclusion