Interferon down-regulation of miR-1225-3p as an antiviral mechanism through modulating Grb2-associated binding protein 3 expression

: Induction of interferons (IFNs) is a central event of antiviral innate immunity. As crucial posttranscriptional regulators, microRNAs (miRNAs) are important for IFN-mediated host defense. Although screening has indicated a substantial number of miRNAs to be differentially expressed after IFN stimulation, the detailed mechanisms of these miRNAs in the antiviral response are underexplored and of great significance. Here, we show that hsa-miR-1225-3p is specifically down-regulated by type I IFN through the IFN/JAK/STAT signaling pathway. Silencing endogenous miR-1225-3p inhibited infection by multiple IFN-susceptible viruses, including hepatitis C virus, Sendai virus, and Newcastle disease virus. In contrast, overexpression of miR-1225-3p impaired the antiviral effect of IFNs and facilitated viral infection. Regarding the mechanism, we identified growth factor receptor-bound protein 2-associated binding protein 3 (GAB3) as a direct target of miR-1225-3p. GAB3 expression was up-regulated by IFN, and overexpression of GAB3 demonstrated potent antiviral effects through enhancing IFN response and virus-triggered innate immune activation. Taken together, our findings reveal the biological function of miR-1225-3p for the first time and propose a novel antiviral regulation pathway in which miRNA and GAB3 participate. This study contributes to the understanding of host miRNA participation in antiviral processes of IFN.