Thanks to the research conducted by scientists from the Laboratory of RNA-Protein Interactions - Dioscuri Center, led by Prof. Gracjan Michlewski, we discovered the mechanism of innate immune response of host cells to RNA viruses. In the latest paper, "TRIM25 inhibits influenza A virus infection, destabilizes viral mRNA, but is redundant for activating the RIG-I pathway," published in Nucleic Acids Research, IIMCB scientists present evidence that human protein TRIM25 inhibits Influenza A virus (IAV) replication, directly binds and destabilises its mRNAs. The 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. 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.