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Nuclear AGO2 Supports Influenza A Virus Infectivity By Downregulating Type-I Interferon Response

GSE248547 Homo sapiens Expression profiling by high throughput sequencing 8 samples Submitted 2025/03/23 Platform GPL24676
Summary
The role of Argonaute (AGO) proteins and the RNA interference (RNAi) machinery in mammalian antiviral response has been debated. Therefore, we set out to investigate how mammalian RNAi impacts influenza A virus (IAV) infection. We demonstrate that IAV infection triggers nuclear accumulation of AGO2, which is directly facilitated by p53 activation. Mechanistically, we show that IAV induces nuclear AGO2 targeting of TRIM71, a proposed AGO2 E3 ligase, and type-I interferon-pathway genes for silencing. Hence, the RNAi machinery is highjacked by the virus to evade the immune system and support viral replication. We demonstrate that the FDA approved drug arsenic trioxide prevents nuclear AGO2:p53 accumulation, thereby increasing interferon response and decreasing viral replication in vitro and in a mouse model in vivo. Our data indicates that targeting the AGO2:p53-mediated silencing of innate immunity may offer a promising strategy to mitigate viral infections.
Published in
Nuclear AGO2 supports influenza A virus replication through type-I interferon regulation
Huang HC, Fong M, Nowak I et al. · Nucleic acids research 2025 · PMID 40219968 · doi:10.1093/nar/gkaf268
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Also filed as BioProject PRJNA1044764 and SRA study SRP474002. Searching any of these in the dataset finder brings you back here.

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