XRN1 Stalling in the 5’ UTR of Hepatitis C Virus and Bovine Viral Diarrhea Virus Is Associated with Dysregulated Host mRNA Stability


Understanding how a persistent virus like Hepatitis C Virus (HCV) interfaces with the cellular machinery during infection can provide significant insights into mechanisms of pathogenesis. We demonstrate that while trying to degrade HCV transcripts, a major cellular exonuclease called XRN1 stalls and gets repressed in the 5’ noncoding region of the viral mRNA. Interestingly, the region where XRN1 stalls in the 5’ UTR includes the viral IRES that is required for translation initiation, uncovering a novel, unexpected function for this well-studied region. Differential mRNA stability is a major regulator of gene expression in cells. Curiously, repression of the cellular XRN1 exonuclease is associated with a general repression of mRNA decay in general in HCV-infected cells. Thus numerous cellular mRNAs are stabilized and accumulate in a dysregulated fashion during HCV infection. Normally short-lived mRNAs are disproportionately affected—including mRNAs that encode immune regulators and oncogenes. Thus, this study suggests a novel role for the 5’ UTR of HCV in molecular pathogenesis—including hepatocellular carcinoma. Furthermore, the 5’ UTR of Bovine Viral Diarrhea virus also represses the XRN1 enzyme and stabilizes cellular mRNA. Therefore a strategy of 5’ UTR-mediated XRN1 repression appears to be conserved among the vector-independent members of the Flaviviridae.


Vyšlo v časopise: XRN1 Stalling in the 5’ UTR of Hepatitis C Virus and Bovine Viral Diarrhea Virus Is Associated with Dysregulated Host mRNA Stability. PLoS Pathog 11(3): e32767. doi:10.1371/journal.ppat.1004708
Kategorie: Research Article
prolekare.web.journal.doi_sk: 10.1371/journal.ppat.1004708

Souhrn

Understanding how a persistent virus like Hepatitis C Virus (HCV) interfaces with the cellular machinery during infection can provide significant insights into mechanisms of pathogenesis. We demonstrate that while trying to degrade HCV transcripts, a major cellular exonuclease called XRN1 stalls and gets repressed in the 5’ noncoding region of the viral mRNA. Interestingly, the region where XRN1 stalls in the 5’ UTR includes the viral IRES that is required for translation initiation, uncovering a novel, unexpected function for this well-studied region. Differential mRNA stability is a major regulator of gene expression in cells. Curiously, repression of the cellular XRN1 exonuclease is associated with a general repression of mRNA decay in general in HCV-infected cells. Thus numerous cellular mRNAs are stabilized and accumulate in a dysregulated fashion during HCV infection. Normally short-lived mRNAs are disproportionately affected—including mRNAs that encode immune regulators and oncogenes. Thus, this study suggests a novel role for the 5’ UTR of HCV in molecular pathogenesis—including hepatocellular carcinoma. Furthermore, the 5’ UTR of Bovine Viral Diarrhea virus also represses the XRN1 enzyme and stabilizes cellular mRNA. Therefore a strategy of 5’ UTR-mediated XRN1 repression appears to be conserved among the vector-independent members of the Flaviviridae.


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Hygiena a epidemiológia Infekčné lekárstvo Laboratórium

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