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

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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: https://doi.org/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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Článek Spatiotemporal Regulation of a T4SS Substrate by the Metaeffector SidJ
Článek Antigenic Properties of the Human Immunodeficiency Virus Envelope Glycoprotein Gp120 on Virions Bound to Target Cells
Článek Dependence of Intracellular and Exosomal microRNAs on Viral Oncogene Expression in HPV-positive Tumor Cells
Článek Identification of a Peptide-Pheromone that Enhances Escape from Host Cell Vacuoles
Článek Impaired Systemic Tetrahydrobiopterin Bioavailability and Increased Dihydrobiopterin in Adult Falciparum Malaria: Association with Disease Severity, Impaired Microvascular Function and Increased Endothelial Activation
Článek Transgenic Expression of the Dicotyledonous Pattern Recognition Receptor EFR in Rice Leads to Ligand-Dependent Activation of Defense Responses
Článek Comprehensive Antigenic Map of a Cleaved Soluble HIV-1 Envelope Trimer
Článek Low Doses of Imatinib Induce Myelopoiesis and Enhance Host Anti-microbial Immunity
Článek Impaired Systemic Tetrahydrobiopterin Bioavailability and Increased Oxidized Biopterins in Pediatric Falciparum Malaria: Association with Disease Severity
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PLOS Pathogens

2015 Číslo 3
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Autori: doc. MUDr. David Zemánek, Ph.D., MUDr. Anna Chaloupka, Ph.D.
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