MicroRNA-122 supports robust innate immunity in hepatocytes by targeting the RTKs/STAT3 signaling pathway.

Hui Xu,Shu-Juan Xie,Yin Zhang,Jian-Hua Yang,Man-Ni Zheng,Hui Zhou,Shi-Jun Xu,Wei-Qi Zhang,Liang-Hu Qu

doi:10.7554/elife.41159

Abstract

MicroRNA-122 (miR-122) is the most abundant microRNA in hepatocytes and a central player in liver biology and disease. Herein, we report a previously unknown role for miR-122 in hepatocyte intrinsic innate immunity. Restoration of miR-122 levels in hepatoma cells markedly enhanced the activation of interferons (IFNs) in response to a variety of viral nucleic acids or simulations, especially in response to hepatitis C virus RNA and poly (I:C). Mechanistically, miR-122 downregulated the phosphorylation (Tyr705) of STAT3, thereby removing the negative regulation of STAT3 on IFN-signaling. STAT3 represses IFN expression by inhibiting interferon regulatory factor 1 (IRF1), whereas miR-122 targets MERTK, FGFR1 and IGF1R, three receptor tyrosine kinases (RTKs) that directly promote STAT3 phosphorylation. This work identifies a miR-122-RTKs/STAT3-IRF1-IFNs regulatory circuitry, which may play a pivotal role in regulating hepatocyte innate immunity. These findings renewed our knowledge of miR-122's function and have important implications for the treatment of hepatitis viruses.

Highlights

Interferon (IFN)-mediated innate immune responses provide a first line of defense against viral infections (Wack et al, 2015)
By measuring the induction of phosphorylated STAT1 (p-STAT1, a marker of IFN signaling activation), melanoma differentiation-associated protein 5 (MDA5, an interferon-stimulated gene (ISG) that is markedly induced upon IFN signaling activation), and IFN mRNAs (IFN-b, type I; IL-29 and IL-28, type III), we found that HepG2 has a relatively strong innate immunity compared to that of Huh7 and Huh7.5.1 (Figure 1—figure supplement 1A,B, Figure 1—source data 1), and may be relatively close to the primary human hepatocytes in innate immune response (Israelow et al, 2014; Thomas et al, 2012)
Transfection with RNAs extracted from HepG2 cells harbouring transient (HBV1.3) or stable (HBV2.15) hepatitis B virus (HBV) replicons (Figure 1—figure supplement 1C, Figure 1—source data 2), in vitro transcribed HBV e-region of HBV RNA (eRNA) (Sato et al, 2015), viral DNA motif derived from the herpes simplex virus (HSV-60), or U-rich single-stranded RNA derived from HIV only induced weak IFN activation (Figure 1A, Figure 1—source data 3)

Summary

Introduction

Interferon (IFN)-mediated innate immune responses provide a first line of defense against viral infections (Wack et al, 2015). HCV induces miR-373, which directly targets JAK1 and IRF9 (Mukherjee et al, 2015), two important components of the Janus kinase-signal transducer and activator of transcription (JAKSTAT) signaling cascade These studies have revealed an interaction between innate immune-related genes and hepatic miRNAs, the roles of miRNAs in regulating hepatocyte innate immunity are far from fully understood. We have dissected the mechanism through which STAT3 represses the IFN response, an important topic in innate immunity These findings renewed our knowledge about miR-122’s role in viral infection and immunity, which has important implications for the treatment of hepatitis viruses

Results

Discussion

Materials and methods

Funding Funder