miR-122 Stimulates Hepatitis C Virus RNA Synthesis by Altering the Balance of Viral RNAs Engaged in Replication versus Translation

Masaki, Takahiro; Arend, Kyle C.; Li, You; Yamane, Daisuke; McGivern, David R.; Kato, Takanobu; Wakita, Takaji; Moorman, Nathaniel J.; Lemon, Stanley M.

doi:10.1016/j.chom.2014.12.014

Cited by 121 publications

(171 citation statements)

References 41 publications

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“…Perhaps more intriguing, miRNA binding could serve as a switch between translation and replication and/or packaging. A recent study suggested that miR-122 competes with binding of cellular factors such as PCBP2 to the HCV 5’ UTR to act as such a switch (Masaki et al, 2015). Future work should also expand on the role, if any, of non-canonical interaction with let-7.…”

Section: Discussionmentioning

confidence: 99%

A Broad RNA Virus Survey Reveals Both miRNA Dependence and Functional Sequestration

Scheel

Luna

Liniger

et al. 2016

Cell Host & Microbe

113

167

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Small non-coding RNAs have emerged as key modulators of viral infection. However, with the exception of hepatitis C virus, which requires the liver-specific microRNA (miRNA)-122, the interactions of RNA viruses with host miRNAs remain poorly characterized. Here, we used crosslinking immunoprecipitation (CLIP) of the Argonaute (AGO) proteins to characterize strengths and specificities of miRNA interactions in the context of 15 different RNA virus infections, including several clinically relevant pathogens. Notably, replication of pestiviruses, a major threat to milk and meat industries, critically depended on the interaction of cellular miR-17 and let-7 with the viral 3’UTR. Unlike canonical miRNA interactions, miR-17 and let-7 binding enhanced pestivirus translation and RNA stability. miR-17 sequestration by pestiviruses conferred reduced AGO binding and functional de-repression of cellular miR-17 targets, thereby altering the host transcriptome. These findings generalize the concept of RNA virus dependence on cellular miRNAs and connect virus-induced miRNA sequestration to host transcriptome regulation.

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Section: Discussionmentioning

confidence: 99%

A Broad RNA Virus Survey Reveals Both miRNA Dependence and Functional Sequestration

Scheel

Luna

Liniger

et al. 2016

Cell Host & Microbe

113

167

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“…miR-122 plays an essential role in the HCV life cycle, directly stimulating viral RNA synthesis while also stabilizing the positivestrand HCV RNA genome and slowing its decay (17,18). Xrn1 and Xrn2 share limited sequence homology restricted to their Nterminal exoribonuclease domains but have very distinct subcellular localization and functions (28).…”

Section: Discussionmentioning

confidence: 99%

“…miR-122 binds two sites in the viral genome close to its 5= terminus, recruiting argonaute 2 protein (AGO2) to the viral RNA (16,17). In addition to acting directly to stimulate viral RNA synthesis (18), miR-122 forms a ternary complex with AGO2 that protects the viral genome from 5= exonucleolytic decay in infected cells (17,19). Thus, supplementing the endogenous abundance of miR-122 in hepatoma cells by transfection of synthetic duplex miR-122 increases the half-life (t 1/2 ) of viral RNA following pharmacologic arrest of new viral RNA synthesis in infected cells, while the opposite effect, a reduction in the HCV RNA t 1/2 , can be induced by transfection of antisense oligoribonucleotides complementary to the miR-122 guide strand (17).…”

Section: Importancementioning

confidence: 99%

Dissecting the Roles of the 5′ Exoribonucleases Xrn1 and Xrn2 in Restricting Hepatitis C Virus Replication

Yamane

Lemon

2015

J Virol

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The replication of hepatitis C virus (HCV) is uniquely dependent on a host microRNA, miR-122. Previous studies using genotype 1a H77S.3 virus demonstrated that miR-122 acts in part by protecting the RNA genome from 5= decay mediated by the cytoplasmic 5= exoribonuclease, Xrn1. However, this finding has been challenged by a recent report suggesting that a predominantly nuclear exoribonuclease, Xrn2, mediates the degradation of genotype 2a JFH1 RNA. Here, we dissect the roles of these two 5= exoribonucleases in restricting the replication of different HCV strains and mediating the decay of HCV RNA. Small interfering RNA (siRNA) depletion experiments indicated that Xrn1 restricts replication of all HCV strains tested: JFH1, H77S.3, H77D (a robustly replicating genotype 1a variant), and HJ3-5 (a genotype 1a/2a chimeric virus). In contrast, the antiviral effects of Xrn2 were limited to JFH1 and H77D viruses. Moreover, such effects were not apparent in cells infected with a JFH1 luciferase reporter virus. Whereas Xrn1 depletion significantly slowed decay of JFH1 and HJ3-5 RNAs, Xrn2 depletion marginally enhanced the JFH1 RNA half-life and had no effect on HJ3-5 RNA decay. The positive effects of Xrn1 depletion on JFH1 replication were largely redundant and nonadditive with those of exogenous miR-122 supplementation, whereas Xrn2 depletion acted additively and thus independently of miR-122. We conclude that Xrn1 is the dominant 5= exoribonuclease mediating decay of HCV RNA and that miR-122 provides protection against it. The restriction of JFH1 and H77D replication by Xrn2 is likely indirect in nature and possibly linked to cytopathic effects of these robustly replicating viruses. IMPORTANCEHCV is a common cause of liver disease both within and outside the United States. Its replication is dependent upon a small, liver-specific noncoding RNA, miR-122. Although this requirement has been exploited for the development of an anti-miR-122 antagomir as a host-targeting antiviral, the molecular mechanisms underpinning the host factor activity of miR-122 remain incompletely defined. Conflicting reports suggest miR-122 protects the viral RNA against decay mediated by distinct cellular 5= exoribonucleases, Xrn1 and Xrn2. Here, we compare the roles of these two exoribonucleases in HCV-infected cells and confirm that Xrn1, not Xrn2, is primarily responsible for decay of RNA in cells infected with multiple virus strains. Our results clarify previously published research and add to the current understanding of the host factor requirement for miR-122. P ersistent infections with hepatitis C virus (HCV) are a common cause of chronic and life-threatening liver diseases, including cirrhosis and hepatocellular carcinoma (1). A positivestrand RNA virus classified within the genus Hepacivirus in the family Flaviviridae, HCV typically infects surreptitiously, causing little overt disease until late in the course of the infection, often several decades later. The virus is largely, if not exclusively, hepatotropic, but viral RNA and p...

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“…Although some previous investigations have shown no differences in the presence and levels of HCV RNA between the tumor and nontumorous liver tissues (15-17), others have reported low to undetectable levels of HCV RNA within the tumor (18-20). Several reports have indicated that miR-122 is an essential cellular host factor for HCV replication (21,22). Initial studies performed in liver cancer, regardless of the etiology, have shown a reduced expression of miR-122 (23, 24), whereas recent reports have demonstrated that its expression in HCV-associated HCC is maintained (25,26) or even increased (27).…”

mentioning

confidence: 99%

Diminished viral replication and compartmentalization of hepatitis C virus in hepatocellular carcinoma tissue

Harouaka

Engle

Wollenberg

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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Analysis of hepatitis C virus (HCV) replication and quasispecies distribution within the tumor of patients with HCV-associated hepatocellular carcinoma (HCC) can provide insight into the role of HCV in hepatocarcinogenesis and, conversely, the effect of HCC on the HCV lifecycle. In a comprehensive study of serum and multiple liver specimens from patients with HCC who underwent liver transplantation, we found a sharp and significant decrease in HCV RNA in the tumor compared with surrounding nontumorous tissues, but found no differences in multiple areas of control non-HCC cirrhotic livers. Diminished HCV replication was not associated with changes in miR-122 expression. HCV genetic diversity was significantly higher in livers containing HCC compared with control non-HCC cirrhotic livers. Tracking of individual variants demonstrated changes in the viral population between tumorous and nontumorous areas, the extent of which correlated with the decline in HCV RNA, suggesting HCV compartmentalization within the tumor. In contrast, compartmentalization was not observed between nontumorous areas and serum, or in controls between different areas of the cirrhotic liver or between liver and serum. Our findings indicate that HCV replication within the tumor is restricted and compartmentalized, suggesting segregation of specific viral variants in malignant hepatocytes.hepatitis C virus | hepatocellular carcinoma | HCV RNA levels | HCV quasispecies | liver H epatitis C virus (HCV) is a hepatotropic, single-stranded RNA virus that replicates in the cytoplasm of hepatocytes and does not integrate into the host genome (1). HCV circulates in vivo as a dynamic distribution of closely related viral variants that are commonly referred to as "quasispecies" (2). Such diversity confers a remarkable advantage to the virus under host selective constraints (3-5). One of the most important features of HCV is its extraordinary ability to persist in up to 80% of infected individuals (6). Approximately 20-30% of chronic HCV carriers develop cirrhosis and its long-term sequelae, including hepatic decompensation and hepatocellular carcinoma (HCC), leading to orthotopic liver transplantation (OLT) or liver-related death (6). The incidence of HCC in the United States has more than tripled over the past 3 decades (7), an alarming trend due primarily, if not exclusively, to HCV infection (8).Although epidemiologic evidence has linked chronic HCV infection to a significantly elevated risk of developing HCC (9), the mechanisms whereby HCV promotes hepatocarcinogenesis remain to be elucidated (10). Whether HCV elicits liver cancer indirectly, through chronic inflammation, fibrosis, and continuous liver regeneration (11), or directly, through the expression of tumor-promoting viral proteins, in a manner analogous to other oncogenic viruses, such as human papillomaviruses and EpsteinBarr virus (12, 13), remains unknown. The major challenges in defining the role of HCV in the pathogenesis of HCC include the inherent limitations of available experimental...

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miR-122 Stimulates Hepatitis C Virus RNA Synthesis by Altering the Balance of Viral RNAs Engaged in Replication versus Translation

Cited by 121 publications

References 41 publications

A Broad RNA Virus Survey Reveals Both miRNA Dependence and Functional Sequestration

A Broad RNA Virus Survey Reveals Both miRNA Dependence and Functional Sequestration

Dissecting the Roles of the 5′ Exoribonucleases Xrn1 and Xrn2 in Restricting Hepatitis C Virus Replication

Diminished viral replication and compartmentalization of hepatitis C virus in hepatocellular carcinoma tissue

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