Nuclear Dicer mediates IFN-b production in response to RNA virus infection

Abstract

Dicer plays an essential role in the RNA-interference (RNAi) pathway. The structure of Dicer is highly conserved across eukaryotic organisms. While the significance of Dicer in regulation of antiviral RNAi in lower eukaryotes and genesis of microRNAs in mammals have been established, it remains largely unclear whether Dicer could also be involved in other innate antiviral pathways, particularly in the nucleus. In this study, we explored the link between nuclear Dicer and transcription initiation of interferon (IFN) regulatory factors in cells infected with nuclear-replicating influenza A virus. Infection of RNA viruses is initially recognized by host pattern recognition receptors (PRRS) which induce antiviral responses, such as production of type I IFN. Many RNA viruses have evolved with antagonistic mechanisms to counteract host antiviral response and it is difficult to study some host antiviral functions using wild type viruses. We examined the role of Dicer under infection by using various RNA viruses defective in antagonizing IFN-β production. Our data showed that the depletion of Dicer has no effect on IRF3 activation but down regulates IFN-β production. Furthermore, over-expression of the constitutively active CARDs from RIG-I in Dicer knockdown cells failed to activate the IFN-b promoter. Using an influenza A virus infection model, we demonstrated that Dicer exerts anti-viral function through modulation of host IFN expressions in the nucleus. It appears that only nuclear-replicating influenza virus, but not the cytoplsmic-replicating Sendai virus, can promote translocation of Dicer to the nucleus. Taken together, our findings suggested that Dicer could induce host antiviral response independent of RIG-I and microRNA pathways. Molecular details for this mechanism will be discussed.