%0 Journal Article %A Hui Xu %A Shi-Jun Xu %A Shu-Juan Xie %A Yin Zhang %A Jian-Hua Yang %A Wei-Qi Zhang %A Man-Ni Zheng %A Hui Zhou %A Liang-Hu Qu %T MicroRNA-122 supports robust innate immunity in hepatocytes by suppressing STAT3 phosphorylation %D 2018 %R 10.1101/250746 %J bioRxiv %P 250746 %X The intrinsic innate immunity of hepatocytes is essential for the control of hepatitis viruses and influences the outcome of antiviral therapy. MicroRNA-122 (miR-122) is the most abundant microRNA in hepatocytes and is a central player in liver biology and disease. However, little is known about the role of miR-122 in hepatocyte innate immunity. Herein, we show that restoring miR-122 levels in hepatoma cells markedly increased the activation of both type III and type I interferons (IFNs) in response to hepatitis C virus (HCV) RNA or poly(I:C). We determined that miR-122 promotes IFN production through down-regulating the tyrosine (Tyr705) phosphorylation of STAT3. We show that STAT3 represses IFN activation by inhibiting interferon regulatory factor 1 (IRF1), which is rate-limiting for maximal IFN expression, especially type III IFNs. Through large-scale screening, we identified that miR-122 targets MERTK, FGFR1 and IGF1R, three oncogenic receptor tyrosine kinases that directly promote STAT3 phosphorylation. These findings reveal a previously unknown role for miR-122 in hepatic immunity and indicate a new potential strategy for treating hepatic infections through targeting STAT3. %U https://www.biorxiv.org/content/biorxiv/early/2018/01/19/250746.full.pdf