MicroRNA-29 stabilizes interferon-gamma mRNA by antagonizing AU-rich element-mediated decay (57.3)

Abstract

Abstract Tight regulation of interferon-gamma (IFN-g) expression is critical for an optimal immune response. IFN-g mRNA levels are attenuated by AU-rich element (ARE)-mediated decay (AMD) via the tristetraprolin (TTP) complex. Here we show that miR-29 targets the 3'untranslated region of IFN-g mRNA and unlike the conventional inhibitory function of miRNAs, increases IFN-g protein expression by stabilizing the mRNA. Through analysis of RNA structure derived by chemoenzymatic probing, we demonstrate that the AMD function is blocked by a miR-29 induced RNA conformational switch that makes the TTP binding site inaccessible. This effectively results in competition between the miRNA-induced silencing complex and TTP for post-transcriptional control of IFN-g gene expression. Our proposed role of miR-29 in stabilizing IFN-g provides a novel molecular mechanism of miRNA regulation and presents new targets for the manipulation of the immune system in the treatment of human diseases.