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

ABSTRACT 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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    • "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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    ABSTRACT: tMicroRNAs (miRNAs) constitute an important class of non-coding RNA implicated in gene expression reg-ulation. More than 1900 miRNA molecules have been identified in humans and their modulation duringviral infection and it is recognized to play a role in latency regulation or in establishing an antiviral state.The liver cells are targets during DENV infection, and alteration of liver functions contributes to severedisease. In this work the miRNAs expression profile of the human hepatoma cell line, Huh-7, infected withDENV-2 was determined using microarray and real-time PCR. Let-7c is one of the miRNAs up-regulatedduring DENV infection in the hepatic Huh-7 as well as in the macrophage-monocytic cell line U937-DC-SIGN. Let-7c overexpression down-regulates both DENV-2 and DENV-4 infection. Additionally, we foundthat the transcription factor BACH1, a let-7c target, is also down-regulated during DENV infection. Inaccordance with this finding, HO-1, the main responsive factor of BACH1 was found up-regulated. Theup-regulation of HO-1 may contribute to the stress oxidative response in infected cells
    Virus Research 01/2015; 196:105-112. DOI:10.1016/j.virusres.2014.11.010 · 2.32 Impact Factor
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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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    ABSTRACT: The P body protein LSm1 stimulates translation and replication of hepatitis C virus (HCV). As the liver-specific microRNA-122 (miR-122) is required for HCV replication and is associated with P bodies, we investigated whether regulation of HCV by LSm1 involves miR-122. Here, we demonstrate that LSm1 contributes to activation of HCV internal ribosome entry site (IRES)-driven translation by miR-122. This role for LSm1 is specialized for miR-122 translation activation, as LSm1 depletion does not affect the repressive function of miR-122 at 3' untranslated region (UTR) sites, or miR-122-mediated cleavage at a perfectly complementary site. We find that LSm1 does not influence recruitment of the microRNA (miRNA)-induced silencing complex to the HCV 5'UTR, implying that it regulates miR-122 function subsequent to target binding. In contrast to the interplay between miR-122 and LSm1 in translation, we find that LSm1 is not required for miR-122 to stimulate HCV replication, suggesting that miR-122 regulation of HCV translation and replication have different requirements. For the first time, we have identified a protein factor that specifically contributes to activation of HCV IRES-driven translation by miR-122, but not to other activities of the miRNA. Our results enhance understanding of the mechanisms by which miR-122 and LSm1 regulate HCV.
    Nucleic Acids Research 10/2013; 42(2). DOI:10.1093/nar/gkt941 · 9.11 Impact Factor
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    • "It is highly and selectively expressed in liver where it regulates lipid metabolism (16). In addition to its natural function, miR-122 plays a pivotal role in the in the life cycle of the liver-tropic hepatitis C virus (HCV) (17,18). MiRNAs can be inhibited from binding their targets by complementary oligonucleotides (antimiRs) (19). "
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    ABSTRACT: MicroRNAs (miRNAs) are short noncoding RNAs, which bind to messenger RNAs and regulate protein expression. The biosynthesis of miRNAs includes two precursors, a primary miRNA transcript (pri-miRNA) and a shorter pre-miRNA, both of which carry a common stem-loop bearing the mature miRNA. MiR-122 is a liver-specific miRNA with an important role in the life cycle of hepatitis C virus (HCV). It is the target of miravirsen (SPC3649), an antimiR drug candidate currently in clinical testing for treatment of HCV infections. Miravirsen is composed of locked nucleic acid (LNAs) ribonucleotides interspaced throughout a DNA phosphorothioate sequence complementary to mature miR-122. The LNA modifications endow the drug with high affinity for its target and provide resistance to nuclease degradation. While miravirsen is thought to work mainly by hybridizing to mature miR-122 and blocking its interaction with HCV RNA, its target sequence is also present in pri- and pre-miR-122. Using new in vitro and cellular assays specifically developed to discover ligands that suppress biogenesis of miR-122, we show that miravirsen binds to the stem-loop structure of pri- and pre-miR-122 with nanomolar affinity, and inhibits both Dicer- and Drosha-mediated processing of miR-122 precursors. This inhibition may contribute to the pharmacological activity of the drug in man.
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