Regulation of hepatitis C virus by microRNA-122: Figure 1

Centre for Biomolecular Sciences, University of Nottingham, University Park, Nottingham, UK.
Biochemical Society Transactions (Impact Factor: 3.19). 01/2009; 36(Pt 6):1220-3. DOI: 10.1042/BST0361220
Source: PubMed


Most metazoan miRNAs (microRNAs) bind to sites in the 3'-UTRs (untranslated regions) of mRNA targets and negatively regulate protein synthesis. The liver-specific miR-122, however, exerts a positive effect on HCV (hepatitis C virus) RNA levels by binding directly to a site in the 5'-UTR of the viral RNA. HCV translation and RNA stability are unaffected, and therefore miR-122 is likely to act at the level of viral replication. The miR-122-binding site in HCV RNA was examined to determine whether the nature of the site is responsible for the unusual mode of action for a miRNA. When the site was placed in the 3'-UTR of a reporter mRNA, miR-122 repressed translation, and therefore the location of the miR-122-binding site dictates its effect on gene expression. Additionally, a second binding site for miR-122 was identified in the HCV 5'-UTR, and miR-122 binding to both sites in the same viral RNA was found to be necessary for viral replication. The two sites are adjacent and are separated by a short spacer, which is largely conserved between HCV genotypes. The binding site requirements for miR-122 to positively regulate HCV replication provide an insight into this unusual mode of miRNA action.

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    • "Furthermore, restoration of miR-122 expression was found to prevent development of liver disease and HCC in mouse models, supporting its tumor-suppressive role [Nassirpour et al., 2013]. However, interestingly, miR-122 has also been shown to play an important role in the life cycle of hepatitis C virus (HCV) and to be an essential host factor for HCV infection [Jopling, 2008; Roberts et al., 2011]. Accordingly, treatment of chronically infected nonhuman primates with a locked nucleic acid (LNA)–modified antisense oligonucleotide complementary to the miR-122 sequence led to a long-lasting suppression of HCV viremia, suggesting that miR-122 represents a potential target for antiviral therapies [Lanford et al., 2010]. "
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    • "On the other hand, other miRNAs can also up-regulate HCV replication where, high expression of miR-122 in the liver, which interacts with the 5 UTR of the viral genome, promotes viral replication in hepatic cells (Jopling et al., 2006; Jopling et al., 2005). Indeed, the expression of miRNA-122 in liver cells is required for viral viability (Jopling, 2008). The gene expression regulation carried out by miRNAs can be mediated by their interaction with RNA sequences present in viral genomes as well as in cellular mRNAs, modulating host factors involved in mechanisms of antiviral response. "
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    • "MicroRNAs (miRNAs) are small (21–23 nt) noncoding RNA molecules that canonically function by binding to partially complementary sites in the 3′UTR of mRNA targets, leading to translational repression and mRNA degradation (6). In contrast, miR-122 regulates HCV by interacting with two adjacent sites in the viral 5′UTR, immediately upstream of the IRES, and positively regulating the viral replication cycle (3,7). "
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