Infection Medicine

The Michlewski team discovers a new mechanism involved in TRIM25’s antiviral activity

We present new evidence that TRIM25 inhibits Influenza A virus (IAV) transcription, directly binds, and destabilises its mRNAs. Our results uncover a new potential mechanism of host cell innate immune response to RNA viruses.

The E3 ubiquitin ligase TRIM25 is a key factor in the innate immune response to RNA viruses. TRIM25 has been shown to play a role in the retinoic-acid inducible gene-1 (RIG-I) pathway, which triggers expression of type 1 interferons upon viral infection. We and others have shown that TRIM25 is an RNA binding protein; however, the role of TRIM25 RNA binding in the innate immune response to RNA viruses is unclear. Here, we demonstrate that influenza A virus infection is inhibited by TRIM25. Surprisingly, this does not seem to involve TRIM25’s E3 ubiquitin ligase activity. Furthermore, we show that in human-derived cultured cells, activation of the RIG-I/interferon type 1 pathway mediated by either an IAV-derived 5’-triphosphate RNA or by IAV itself does not require TRIM25 activity. Additionally, we present new evidence that instead of TRIM25 directly inhibiting IAV transcription it binds and destabilizes IAV mRNAs. Finally, we show that direct tethering of TRIM25 to RNA is sufficient to downregulate the targeted RNA. In summary, our results uncover a potential mechanism that TRIM25 uses to inhibit IAV infection and regulate RNA metabolism.

Model of TRIM25 sensing and inhibiting IAV infection by controlling viral mRNA stability
Model of TRIM25 sensing and inhibiting IAV infection by controlling viral mRNA stability.During IAV infection, TRIM25 binds to positive strand RNAs and triggers mRNA degradation, which in turn might be one of the factors that contributes to inhibition of viral replication. Our results also predict additional, E3 ligase-independent mechanisms, of TRIM25-mediated control of IAV infection.