Beta-Arrestin 2 As An Activator Of Cgas-Sting Signaling And Target Of Viral Immune Evasion

Virus infection may induce excessive interferon (IFN) responses that can lead to host tissue injury or even death. beta -arrestin 2 regulates multiple cellular events through the G protein-coupled receptor (GPCR) signaling pathways. Here we demonstrate that beta -arrestin 2 also promotes virus-induced production of IFN-beta and clearance of viruses in macrophages. beta -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 beta -arrestin 2 at Lys171 facilitates the activation of the cGAS-STING signaling and the production of IFN-beta. In vitro, viral infection induces the degradation of beta -arrestin 2 to facilitate immune evasion, while a beta -blocker, carvedilol, rescues beta -arrestin 2 expression to maintain the antiviral immune response. Our results thus identify a viral immune-evasion pathway via the degradation of beta -arrestin 2, and also hint that carvedilol, approved for treating heart failure, can potentially be repurposed as an antiviral drug candidate. Excessive interferon (IFN) responses often follow viral infection to induce pathology or even death. Here the authors show that a signaling adaptor, beta -arrestin 2, enhances the cGAS/STING innate immunity signaling pathway to promote IFN-beta production, but may be degraded in infected cells to serve as a target of viral immune evasion.