XRN1 stalling in the 5' UTR of Hepatitis C virus and Bovine Viral Diarrhea virus is associated with dysregulated host mRNA stability

We demonstrate that both Hepatitis C virus (HCV) and Bovine Viral Diarrhea virus (BVDV) contain regions in their 5' UTRs that stall and repress the enzymatic activity of the cellular 5'-3' exoribonuclease XRN1, resulting in dramatic changes in the stability of cellular mRNAs. We used...

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Bibliographic Details
Published in:PLoS pathogens 2015-03, Vol.11 (3), p.e1004708-e1004708
Main Authors: Moon, Stephanie L, Blackinton, Jeffrey G, Anderson, John R, Dozier, Mary K, Dodd, Benjamin J T, Keene, Jack D, Wilusz, Carol J, Bradrick, Shelton S, Wilusz, Jeffrey
Format: Article
Language:English
Subjects:
5' Untranslated Regions - genetics
Animals
Binding sites
Blotting, Western
Cattle
Cell Line
Diarrhea
Diarrhea Viruses, Bovine Viral - genetics
Diarrhea Viruses, Bovine Viral - pathogenicity
Exoribonucleases - metabolism
Gene expression
Genetic aspects
Genomes
Health aspects
Hepacivirus - genetics
Hepacivirus - pathogenicity
Hepatitis
Hepatitis C virus
Host-Parasite Interactions - genetics
Host-virus relationships
Humans
Infections
Liver cancer
Messenger RNA
Microtubule-Associated Proteins - metabolism
Pathogenesis
Polymerase Chain Reaction
Proteins
RNA Stability - genetics
RNA, Messenger
Standard deviation
Transfection
Virus Replication - genetics
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Summary:We demonstrate that both Hepatitis C virus (HCV) and Bovine Viral Diarrhea virus (BVDV) contain regions in their 5' UTRs that stall and repress the enzymatic activity of the cellular 5'-3' exoribonuclease XRN1, resulting in dramatic changes in the stability of cellular mRNAs. We used biochemical assays, virus infections, and transfection of the HCV and BVDV 5' untranslated regions in the absence of other viral gene products to directly demonstrate the existence and mechanism of this novel host-virus interaction. In the context of HCV infection, we observed globally increased stability of mRNAs resulting in significant increases in abundance of normally short-lived mRNAs encoding a variety of relevant oncogenes and angiogenesis factors. These findings suggest that non-coding regions from multiple genera of the Flaviviridae interfere with XRN1 and impact post-transcriptional processes, causing global dysregulation of cellular gene expression which may promote cell growth and pathogenesis.
ISSN:1553-7374
1553-7366
1553-7374
DOI:10.1371/journal.ppat.1004708