Central role of interferon regulatory factor-1 (IRF-1) in controlling retinoic acid inducible gene-I (RIG-I) expression

Retinoic acid inducible gene-I (RIG-1) functions as the first line of defense against viral infection by sensing dsRNA and inducing type I interferon (IFN) production. The expression of RIG-I itself is induced by IFN-alpha/beta and dsRNA. To comprehend the molecular mechanism of expression regulation, we cloned the RIG-1 promoter and analyzed its activity upon IFN-beta and dsRNA treatment. Under basal condition, RIG-1 mRNA level and promoter activity were significantly higher in normal cells versus their tumor counterparts. In both normal and cancer cells, RIG-1 expression was induced by IFN-beta and dsRNA. A single IRF-I binding site in the proximal promoter functioned as a crucial regulator of basal, IFN-beta- and dsRNA-mediated induction of the RIG-1 promoter. IFN-beta and dsRNA treatment increased IRF-I binding to the RIG-1 promoter. IRF-I expression was also higher in normal cells than in cancer cells and it was induced by IFN-beta with similar kinetics as RIG-1. These results confirm that by controlling RIG-1 expression, IRF-I plays an essential role in anti-viral immunity. IRF-I is a tumor suppressor and the expression profile of RIG-1 together with its regulation by IRF-I and the presence of a caspase-recruitment domain in RIG-1 suggest that RIG-1 might also possess tumor suppressor properties.