Various miRNAs compensate the role of miR-122 on HCV replication

Abstract

One of the determinants for tissue tropism of hepatitis C virus (HCV) is miR-122, a liver-specific microRNA. Recently, it has been reported that interaction of miR-122 to HCV RNA induces a conformational change of the 5'UTR internal ribosome entry site (IRES) structure to form stem-loop II structure (SLII) and hijack of translating 80S ribosome through the binding of SLIII to 40S subunit, which leads to efficient translation. On the other hand, low levels of HCV-RNA replication have also been detected in some non-hepatic cells; however, the details of extrahepatic replication remain unknown. These observations suggest the possibility that miRNAs other than miR-122 can support efficient replication of HCV-RNA in nonhepatic cells. Here, we identified a number of such miRNAs and show that they could be divided into two groups: those that bind HCV-RNA at two locations (miR-122 binding sites I and II), in a manner similar to miR-122 (miR-122-like), and those that target a single site that bridges sites I and II and masking both G28 and C29 in the 5'UTR (non-miR-122-like). Although the enhancing activity of these non-hepatic miRNAs were lower than those of miR-122, substantial expression was detected in various normal tissues. Furthermore, structural modeling indicated that both miR-122-like and non-miR-122-like miRNAs not only can facilitate the formation of an HCV IRES SLII but also can stabilize IRES 3D structure in order to facilitate binding of SLIII to the ribosome. Together, these results suggest that HCV facilitates miR-122-independent replication in non-hepatic cells through recruitment of miRNAs other than miR-122. And our findings can provide a more detailed mechanism of miR-122dependent enhancement of HCV-RNA translation by focusing on IRES tertiary structure.

Enhanced virus translation enables miR-122-independent Hepatitis C Virus propagation

“…However, it is still unclear whether these mutants are capable of usurping other microRNAs in the cell for their propagation. A recent report suggests that HCV replication can be supported by other miRNAs in a miR-122-like (miR-504-3p, miR-574-5p, and miR-1236-5p) and non-miR-122-like manner (miR-25-5p and miR-4730) (39). Thus, we tested for the impact of other miRNAs on the replication of HCV mutants previously reported as capable of replicating independently of miR-122 by assessing their replication in Huh 7.5 Drosha knockout (KO) cells ( Fig.…”

“…Prediction software suggests that the 5’ UTR RNA of the mutants has a greater propensity to form the active HCV IRES even in the absence of miR-122 (11, 12) ( Fig. 1 ), but a recent report has also highlighted the possibility of binding of other microRNAs to the 5’ UTR of the viral genome (39).…”

The Relevance of MicroRNAs in the Pathogenesis and Prognosis of HCV-Disease: The Emergent Role of miR-17-92 in Cryoglobulinemic Vasculitis

“…Thus, the activation of translation via IRES is promoted by the AGO protein containing the miRNA-induced silencing complex (miRISC). The interaction between miR-122-miRISC and HCV-RNA results in miR-122 sequestration, preventing its binding with host targets and promoting HCV replication [12].…”

“…Moreover, a variant of HCV genotype 2 carrying a G28A substitution in the 5 end exhibits efficient RNA replication in the absence of miR-122, while this mutation does not occur when miR-122 levels are abundant [16]. In fact, Ono and colleagues demonstrated that in the absence of miR-122, other miRNAs could interact with the HCV genome promoting its replication and this may be relevant in the pathogenesis of extrahepatic manifestations [12].…”

“…The microRNAs involved in the HCV life cycle and their biological significance are reported in Table 1. [9,10] Together with the Argonaute protein (AGO) stabilizes and protects the uncapped viral genome from degradation [11] Interaction between miR-122-miRISC-HCV-RNA results in miR-122 sequestration, preventing its binding with host targets and promoting HCV replication [12] DCAF1 targets miR-122 and negatively regulates HCV IRES-mediated translation [15] miR-125b-5p Controversial Downregulates HuR which promotes HCV replication [24] Inhibits miR-125b-5p decreasing HCV expression at both RNA and protein levels [25] miR-130a inhibition Inhibits the ATG5 protein that upregulates the expression of type I IFN and of molecules involved in innate immune response [20][21][22] HCV replication is inhibited through the reduced production of ATP and other glycolytic intermediates [23] miR-199a-5p enhancement Stimulates pro-survival pathways like PI3K/Akt, Ras/ERK, and Wnt/β-catenin [18] miR-215 enhancement Inactivates NF-κB pathway by inhibiting TRIM22 [17] miR-491 enhancement Low levels of miR-491 reduced the inhibition of PI3K/AKT pathway which is involved in the maintenance of HCV replication [19]…”