Argonaute 2 inhibits RIG-I signaling via competition for viral RNA binding

Honglian Liu; Yingyin Liao; Fei Yu; Leo Ngo-Shing Li; Yajie Zhang; Lin Zhu; Guangshan Xie; Jiayan Liu; Siwen Liu; Shaofeng Deng; Rachel Chun-Yee Tam; Wenjun Song; Pin Chen; Xiaofeng Huang; Conor J Cremin; Yixin Chen; Min Zheng; Pui Wang; Zongwei Cai; Kwok-Yung Yuen; Honglin Chen; Bobo Wing-Yee Mok

doi:10.1016/j.isci.2025.113391

Argonaute 2 inhibits RIG-I signaling via competition for viral RNA binding

iScience. 2025 Aug 19;28(9):113391. doi: 10.1016/j.isci.2025.113391. eCollection 2025 Sep 19.

Authors

Honglian Liu^{1

2

3}, Yingyin Liao^{1

2}, Fei Yu^{1

4

5}, Leo Ngo-Shing Li⁴, Yajie Zhang⁴, Lin Zhu⁶, Guangshan Xie⁶, Jiayan Liu^{1

4}, Siwen Liu^{1

2}, Shaofeng Deng^{1

2}, Rachel Chun-Yee Tam^{1

2}, Wenjun Song^{1

4}, Pin Chen¹, Xiaofeng Huang^{1

7}, Conor J Cremin¹, Yixin Chen⁸, Min Zheng^{1

9}, Pui Wang^{1

2}, Zongwei Cai⁶, Kwok-Yung Yuen^{1

2

4}, Honglin Chen^{1

2

4}, Bobo Wing-Yee Mok^{1

2

4}

Affiliations

¹ Department of Microbiology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Pokfulam, Hong Kong, P.R. China.
² State Key Laboratory for Emerging Infectious Diseases, The University of Hong Kong, Pokfulam, Hong Kong, P.R. China.
³ Shenzhen Senior High School WENBO High School, Shenzhen, P.R. China.
⁴ Centre for Virology, Vaccinology and Therapeutics Limited, The University of Hong Kong, Pokfulam, Hong Kong, P.R. China.
⁵ Department of Laboratory Medicine, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, P.R. China.
⁶ State Key Laboratory of Environmental and Biological Analysis, Hong Kong Baptist University, Kowloon, Hong Kong, P.R. China.
⁷ Weill Cornell Medicine, New York, NY, USA.
⁸ State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics and National Institute of Diagnostics and Vaccine Development in Infectious Diseases, School of Life Sciences, School of Public Health, Xiamen University, Xiamen, P.R. China.
⁹ Institute of Infectious Diseases, Shenzhen Bay Laboratory, Shenzhen, P.R. China.

Abstract

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.

Keywords: Biological sciences; Microbiology; Natural sciences; Pharmacology; Virology.