Department of Gastroenterology and Hepatology, Erasmus MC-University Medical Center, Rotterdam, The Netherlands.
Translational Liver Research, Department of Medical Cell Biophysics, Technical Medical Centre, Faculty of Science and Technology, University of Twente, Enschede, The Netherlands.
Gut Microbes. 2021 Jan-Dec;13(1):1959839. doi: 10.1080/19490976.2021.1959839.
Although cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) signaling has been well recognized in defending DNA viruses, the role of cGAS-STING signaling in regulating infection of RNA viruses remains largely elusive. Noroviruses, as single-stranded RNA viruses, are the main causative agents of acute viral gastroenteritis worldwide. This study comprehensively investigated the role of cGAS-STING in response to murine norovirus (MNV) infection. We found that STING agonists potently inhibited MNV replication in mouse macrophages partially requiring the JAK/STAT pathway that induced transcription of interferon (IFN)-stimulated genes (ISGs). Loss- and gain-function assays revealed that both cGAS and STING were necessary for host defense against MNV propagation. Knocking out cGAS or STING in mouse macrophages led to defects in induction of antiviral ISGs upon MNV infection. Overexpression of cGAS and STING moderately increased ISG transcription but potently inhibited MNV replication in human HEK293T cells ectopically expressing the viral receptor CD300lf. This inhibitory effect was not affected by JAK inhibitor treatment or expression of different MNV viral proteins. Interestingly, STING but not cGAS interacted with mouse RIG-I, and attenuated its N-terminus-mediated anti-MNV effects. Our results implicate an essential role for mouse cGAS and STING in regulating innate immune response and defending MNV infection. This further strengthens the evidence of cGAS-STING signaling in response to RNA virus infection.
尽管环鸟苷酸-腺苷酸合酶（cGAS）-干扰素基因刺激物（STING）信号通路在防御 DNA 病毒方面已得到充分认识，但 cGAS-STING 信号通路在调控 RNA 病毒感染中的作用在很大程度上仍不清楚。诺如病毒是单链 RNA 病毒，是全球急性病毒性胃肠炎的主要病原体。本研究全面研究了 cGAS-STING 在应对鼠诺如病毒（MNV）感染中的作用。我们发现，STING 激动剂可有效抑制小鼠巨噬细胞中的 MNV 复制，部分需要 JAK/STAT 通路诱导干扰素（IFN）刺激基因（ISGs）的转录。缺失和功能获得实验表明，cGAS 和 STING 均对宿主抵抗 MNV 增殖至关重要。敲除小鼠巨噬细胞中的 cGAS 或 STING 会导致 MNV 感染时抗病毒 ISGs 的诱导缺陷。cGAS 和 STING 的过表达适度增加了 ISG 的转录，但可强烈抑制人 HEK293T 细胞中表达病毒受体 CD300lf 的 MNV 复制。这种抑制作用不受 JAK 抑制剂处理或不同 MNV 病毒蛋白表达的影响。有趣的是，STING 而不是 cGAS 与小鼠 RIG-I 相互作用，并减弱其 N 端介导的抗 MNV 作用。我们的研究结果表明，cGAS 和 STING 在调节固有免疫反应和抵抗 MNV 感染中发挥重要作用。这进一步加强了 cGAS-STING 信号通路在应对 RNA 病毒感染中的作用。
