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 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.
Department of Microbiology, Immunology and Pathology, Colorado State University, Fort Collins, Colorado, United States of America.
Stephanie L
SL
Moon
Department of Molecular Genetics and Microbiology, Duke University Medical Center, Durham, North Carolina, United States of America.
Jeffrey G
JG
Blackinton
Department of Microbiology, Immunology and Pathology, Colorado State University, Fort Collins, Colorado, United States of America.
John R
JR
Anderson
Department of Microbiology, Immunology and Pathology, Colorado State University, Fort Collins, Colorado, United States of America.
Mary K
MK
Dozier
Department of Microbiology, Immunology and Pathology, Colorado State University, Fort Collins, Colorado, United States of America.
Benjamin J T
BJ
Dodd
Department of Molecular Genetics and Microbiology, Duke University Medical Center, Durham, North Carolina, United States of America.
Jack D
JD
Keene
Department of Microbiology, Immunology and Pathology, Colorado State University, Fort Collins, Colorado, United States of America.
Carol J
CJ
Wilusz
Department of Molecular Genetics and Microbiology, Duke University Medical Center, Durham, North Carolina, United States of America.
Shelton S
SS
Bradrick
Department of Microbiology, Immunology and Pathology, Colorado State University, Fort Collins, Colorado, United States of America.
Jeffrey
J
Wilusz
D020121:5' Untranslated Regions / Q000235:genetics; D000818:Animals; D015153:Blotting, Western; D002417:Cattle; D002460:Cell Line; D001908:Diarrhea Viruses, Bovine Viral / Q000235:genetics / Q000472:pathogenicity*; D005095:Exoribonucleases / Q000378:metabolism*; D016174:Hepacivirus / Q000235:genetics / Q000472:pathogenicity*; D006790:Host-Parasite Interactions / Q000235:genetics*; D006801:Humans; D008869:Microtubule-Associated Proteins / Q000378:metabolism*; D016133:Polymerase Chain Reaction; D020871:RNA Stability / Q000235:genetics*; D012333:RNA, Messenger; D014162:Transfection; D014779:Virus Replication / Q000235:genetics*
D020121:5' Untranslated Regions; D008869:Microtubule-Associated Proteins; D012333:RNA, Messenger; D005095:Exoribonucleases; C470512:XRN1 protein, human