Department of Immunology, School of Basic Medical Sciences & Shanghai Public Health Clinical Center, Key Laboratory of Medical Molecular Virology of MOE/MOH, Fudan University, Shanghai, 200032, China.
Department of Microbiology and Biochemical Pharmacy, National Engineering Research Centre of Immunological Products, College of Pharmacy, Army Medical University, Chongqing, 400038, China.
Nat Commun. 2020 Nov 26;11(1):6000. doi: 10.1038/s41467-020-19849-9.
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.
病毒感染可能会诱导过度的干扰素（IFN）反应，从而导致宿主组织损伤甚至死亡。β-arrestin 2 通过 G 蛋白偶联受体（GPCR）信号通路调节多种细胞事件。在这里，我们证明β-arrestin 2 还可以促进巨噬细胞中病毒诱导的 IFN-β产生和病毒清除。β-arrestin 2 与环鸟苷酸-腺苷酸合酶（cGAS）相互作用，并增加 dsDNA 与 cGAS 的结合，以增强环鸟苷酸-腺苷酸（cGAMP）的产生和干扰素基因刺激物（STING）和先天免疫反应。在机制上，β-arrestin 2 在 Lys171 处的去乙酰化促进了 cGAS-STING 信号的激活和 IFN-β的产生。在体外，病毒感染诱导β-arrestin 2 的降解，以促进免疫逃逸，而β受体阻滞剂卡维地洛则可以挽救β-arrestin 2 的表达，维持抗病毒免疫反应。因此，我们的研究结果确定了一种通过β-arrestin 2 降解的病毒免疫逃逸途径，并且还暗示了已被批准用于治疗心力衰竭的卡维地洛可被重新用于作为抗病毒药物的候选药物。
