MicroRNA-29 Stabilizes IFN-γ mRNA by inhibiting GW182 (174.5)

Abstract Tight regulation of interferon-gamma (IFN-γ) expression is critical for an optimal immune response. We have extensively studied the mechanisms responsible for the post-transcriptional regulation of IFN-γ expression. AU-rich element (ARE)-mediated decay (AMD) via the tristetraprolin (TTP) complex is responsible for robust degradation of the IFN-γ mRNA. We found that microRNA-29 (miR-29) targets the IFN-γ 3’UTR and, unlike the conventional inhibitory miRNAs, stabilizes the mRNA. Resolution of the secondary structure showed that the ARE and miR-29 binding site are in close proximity and a series of experiments manipulating the RNA structure revealed that this proximity enables miR-29 to antagonize TTP degradation. Interestingly, miR-29 is unable to degrade the mRNA even in the absence of TTP. Recently we have found that GW182, a major degradation protein in the miRISC, is unable to be recruited to the mRNA as a result of the location of the miR-29 binding site in the secondary structure. The ability of miR-29 to stabilize the IFN-γ mRNA demonstrates a novel molecular mechanism of miRNA regulation.