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

Yihua Zhang, Manman Li, Liuyan Li, Gui Qian, Yu Wang, Zijuan Chen, Jing Liu, Chao Fang, Feng Huang, Daqiao Guo, Quanming Zou, Yiwei Chu and Dapeng Yan ()
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Yihua Zhang: Fudan University
Manman Li: Fudan University
Liuyan Li: Fudan University
Gui Qian: Fudan University
Yu Wang: Army Medical University
Zijuan Chen: Fudan University
Jing Liu: Fudan University
Chao Fang: Fudan University
Feng Huang: Capital Medical University
Daqiao Guo: Fudan University
Quanming Zou: Army Medical University
Yiwei Chu: Fudan University
Dapeng Yan: Fudan University

Nature Communications, 2020, vol. 11, issue 1, 1-15

Abstract: 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.

Date: 2020
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DOI: 10.1038/s41467-020-19849-9

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