Liu Honglian, Liao Yingyin, Yu Fei, Li Leo Ngo-Shing, Zhang Yajie, Zhu Lin, Xie Guangshan, Liu Jiayan, Liu Siwen, Deng Shaofeng, Tam Rachel Chun-Yee, Song Wenjun, Chen Pin, Huang Xiaofeng, Cremin Conor J, Chen Yixin, Zheng Min, Wang Pui, Cai Zongwei, Yuen Kwok-Yung, Chen Honglin, Mok Bobo Wing-Yee
Department of Microbiology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Pokfulam, Hong Kong, P.R. China.
State Key Laboratory for Emerging Infectious Diseases, The University of Hong Kong, Pokfulam, Hong Kong, P.R. China.
iScience. 2025 Aug 19;28(9):113391. doi: 10.1016/j.isci.2025.113391. eCollection 2025 Sep 19.
Interferon (IFN)-dependent responses constitute a critical initial defense against viruses in mammalian cells, while RNA interference (RNAi) acts as an additional strategy to combat invading viral pathogens. Investigating the functionality of mammalian Argonaute 2 (AGO2), an essential component of the RNA-induced silencing complex, we found it to negatively modulate influenza A virus infection-induced RIG-I-mediated antiviral signaling. AGO2 depletion in human cell lines significantly enhanced the RNA virus-triggered phosphorylation of IRF3 and downstream antiviral gene activation. Interestingly, this negative regulation occurred independently of gene silencing via canonical RNA silencing pathways and instead involved the binding of AGO2 to viral RNA molecules carrying 5'-triphosphates or cytosolic RIG-I agonists. These findings highlight AGO2's crucial role in balancing antiviral signaling activation and restricting virus infection to prevent excessive immune responses.
干扰素（IFN）依赖性反应是哺乳动物细胞抵御病毒的关键初始防御机制，而RNA干扰（RNAi）则作为对抗入侵病毒病原体的额外策略。在研究RNA诱导沉默复合体的重要组成部分——哺乳动物AGO2的功能时，我们发现它对甲型流感病毒感染诱导的RIG-I介导的抗病毒信号传导具有负调节作用。人细胞系中AGO2的缺失显著增强了RNA病毒触发的IRF3磷酸化及下游抗病毒基因的激活。有趣的是，这种负调节独立于经典RNA沉默途径的基因沉默发生，而是涉及AGO2与携带5'-三磷酸的病毒RNA分子或胞质RIG-I激动剂的结合。这些发现突出了AGO2在平衡抗病毒信号激活和限制病毒感染以防止过度免疫反应方面的关键作用。
