MicroRNA let-7b expression is induced by infection of hepatitis C virus (HCV) and is involved in the regulation of HCV replication by directly targeting the HCV genome. The current study demonstrated that let-7b directly targets negative regulators of type I interferon (IFN) signaling thereby limiting HCV replication in the early stage of HCV infection. Let-7b-regulated genes which are involved in host cellular responses to HCV infection were unveiled by microarray profiling and bioinformatic analyses followed by various molecular and cellular assays using Huh7 cells expressing wild type or the seed region-mutated let-7b. Let-7b targeted the cytokine signaling 1 (SOCS1) protein, a negative regulator of JAK/STAT signaling, which then enhanced STAT1-Y701 phosphorylation leading to increased expression of the downstream interferon stimulated genes (ISGs). Let-7b augmented RIG-I signaling, but not MDA5, to phosphorylate and nuclear translocate IRF3 leading to increased expression of IFN-β. Let-7b directly targeted the ATG12 and IKKα transcripts and reduced the interaction of the ATG5-ATG12 conjugate and RIG-I leading to increased expression of IFN, which may further stimulate JAK/STAT signaling. Let-7b induced by HCV infection elicits dual effects on IFN expression and signaling, along with targeting the coding sequences of NS5B and 5'-UTR of HCV genome, limited HCV RNA accumulation in the early stage of HCV infection. Controlling let-7b expression is thereby crucial in the intervention of HCV infection.
Importance: HCV is a leading cause of liver disease, with an estimated 71 million people infected worldwide. During HCV infection, type I IFN signaling displays potent anti-viral and immuno-modulatory effects. Host factors, including microRNAs, play a role in up-regulating IFN signaling to limit HCV replication. Let-7b is a liver abundant miRNA that is induced by HCV infection and targets the HCV genome to suppress HCV RNA accumulation. In this study, we demonstrated that let-7b, as a positive regulator of type I IFN signaling, plays dual roles in against HCV replication by increasing the expression of IFN and ISRE-driven ISGs in the early stage of HCV infection. This study sheds new insight into understanding the role of let-7b in combatting HCV infection. Clarifying IFN signaling regulated by miRNA during the early phase of HCV infection may help researchers understand the initial defense mechanisms to other RNA viruses.
CXCL10 Decreases GP73 Expression in Hepatoma Cells at the Early Stage of Hepatitis C Virus (HCV) Infection
