Hepatitis C Virus-Mediated Enhancement of MicroRNA miR-373 Impairs the JAK/STAT Signaling Pathway

Abstract

Hepatitis C virus (HCV) is a serious global health problem and establishes chronic infection in a significant number of infected humans worldwide. Interferon (IFN) and IFN-stimulated genes (ISGs) are amplified during HCV infection but fail to eliminate virus from the liver in a large number of infected patients, and the mechanism is not fully understood. MicroRNAs (miRNAs) have been implicated in the control of many biological processes, including IFN signaling. To gain more insights into the role of cellular miRNAs in possible countermeasures of HCV for suppression of the host antiviral response, a miRNA array was performed by using primary human hepatocytes infected with in vitro cell culture-grown HCV. A group of miRNAs were modulated in HCV-infected primary human hepatocytes. We focused on miR-373, as this miRNA was significantly upregulated in HCV-infected primary human hepatocytes. Here, we analyzed the function of miR-373 in the context of HCV infection. HCV infection upregulates miR-373 expression in hepatocytes and HCV-infected liver biopsy specimens. Furthermore, we discovered that miR-373 directly targets Janus kinase 1 (JAK1) and IFN-regulating factor 9 (IRF9), important factors in the IFN signaling pathway. The upregulation of miR-373 by HCV also inhibited STAT1 phosphorylation, which is involved in ISG factor 3 (ISGF3) complex formation and ISG expression. The knockdown of miR-373 in hepatocytes enhanced JAK1 and IRF9 expression and reduced HCV RNA replication. Taken together, our results demonstrated that miR-373 is upregulated during HCV infection and negatively regulated the type I IFN signaling pathway by suppressing JAK1 and IRF9. Our results offer a potential therapeutic approach for antiviral intervention. H epatitis C virus is a member of the Hepacivirus genus of theFlaviviridae family and is represented by seven major genotypes. The virion contains a 9.6-kb single-stranded RNA genome of positive polarity, with highly invariant 5= and 3= untranslated regions (UTRs) flanking a long open reading frame (ORF) that is translated via an internal ribosome entry site (IRES) (1). The resulting polyprotein is processed by viral and cellular proteases to yield structural (core, E1, and E2/p7) and nonstructural (NS2, NS3, NS4A, NS4B, NS5A, and NS5B) proteins.HCV infection is one of the main causes of chronic liver disease. It is estimated that ϳ200 million people are chronically infected with HCV worldwide (2, 3). Chronic HCV infection is linked to a deregulation of innate and adaptive immune signaling mechanisms (4). Despite progress in understanding immunity against HCV infection and its pathogenesis along with the development of highly effective direct-acting antivirals (DAAs), a prophylactic anti-HCV vaccine is still lacking, and at least 2 million new HCV infections occur each year (5).MicroRNAs (miRNAs) are a class of ϳ18-to 22-nucleotidelong noncoding RNA molecules that function through posttranscriptional regulation of gene expression. The production of miRNAs requires several processi...

MicroRNA 373 Facilitates the Replication of Porcine Reproductive and Respiratory Syndrome Virus by Its Negative Regulation of Type I Interferon Induction

“…In addition, previous studies have shown miR-373 could inhibit the type I IFN receptor signaling pathway by targeting IRF9 (36), and our results also showed that IFNAR1 and IFNAR2 were potential target genes of miR-373, which indicated that miR-373 also targets IFNAR1 and IFNAR2 for its inhibiting the type I IFN receptor signaling pathway (Fig. 4).…”

“…miR-373 could act as an oncogene or a tumor suppressor in different cancers (55). There are also a few reports that miR-373 could enhance the replication of HBV (35) and HCV (36). Here, we found evidence that miR-373 facilitated the replication of PRRSV, and we also investigated the mechanisms.…”

“…*, P Ͻ 0.05; **, P Ͻ 0.01; ***, P Ͻ 0.001. and PRRSV titers (data not shown), which indicated that NFIA, NFIB, IRAK1, IRAK4, IRF1, IRF9, IFNAR1, and IFNAR2 are involved in PRRSV replication regulated by miR-373. Previous studies have shown that NFIB (35) and IRF9 (36) were the target genes of miR-373, so NFIA, NFIB, IRAK1, IRAK4, IRF1, and IRF9 were selected to confirm that the potential target genes described above were also the target genes of miR-373.…”

MicroRNA-30c Modulates Type I IFN Responses To Facilitate Porcine Reproductive and Respiratory Syndrome Virus Infection by Targeting JAK1

“…However, MLV suppresses the activation of ISG15 and ISG56 induced by IFNs in MARC-145 cells, implying that other mechanisms might contribute to the impairment of IFN-I signaling during PRRSV infection (43). Cellular miRNAs were shown to be used by viruses to evade IFN-I-mediated antiviral responses in host cells (18,21,44,45). However, whether miRNAs participate in PRRSV-mediated evasion of IFN-I-mediated antiviral responses remains elusive.…”

HCV infection, IFN response and the coding and non-coding host cell genome

“…They are increased by infection to target key viral sensors, mediators of the IFN activation and signaling or antiviral genes. Examples of this include targeting of TLR3 by miR-758, targeting of factors involved in the TLR signaling such as MyD88 and IRAK1 by miR-21, targeting of JAK1 and IRF9 by miR-373(Mukherjee et al, 2015) or targeting of the antiviral factor IFITM1 by miR-130a(Bhanja Chowdhury et al, 2012).…”