Nuclear RNAi Modulates Influenza A Virus Infectivity By Downregulating Type-I Interferon Response
Huang, H.-C.; Lobo, V.; Schon, K.; Nowak, I.; Westholm, J. O.; Fernandez, C.; Patel, A. A.; Wiel, C.; Sayin, V. I.; Anastasakis, D. G.; Angeletti, D.; Sarshad, A.
Show abstract
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 reveal 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. Accordingly, Tp53-/- mice do not accumulate nuclear AGO2 and demonstrate decreased susceptibility to IAV infection. Hence, the RNAi machinery is highjacked by the virus to evade the immune system and support viral replication. Furthermore, the FDA approved drug arsenic trioxide, which prevents p53 tetramerization and nuclear translocation, increases interferon response and decreases 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.
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