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

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.