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Proc Natl Acad Sci U S A. 2018 Aug 7;115(32):8197-8202. doi: 10.1073/pnas.1802326115. Epub 2018 Jul 23.

RNA triphosphatase DUSP11 enables exonuclease XRN-mediated restriction of hepatitis C virus.

Author information

1
Center for Systems and Synthetic Biology, Department of Molecular Biosciences, The University of Texas at Austin, Austin, TX 78712-0162.
2
LaMontagne Center for Infectious Disease, Department of Molecular Biosciences, The University of Texas at Austin, Austin, TX 78712-0162.
3
Department of Microbiology, The University of Chicago, Chicago, IL 60637.
4
Center for Systems and Synthetic Biology, Department of Molecular Biosciences, The University of Texas at Austin, Austin, TX 78712-0162; chris_sullivan@austin.utexas.edu.

Abstract

Seventy percent of people infected with hepatitis C virus (HCV) will suffer chronic infection, putting them at risk for liver disease, including hepatocellular carcinoma. The full range of mechanisms that render some people more susceptible to chronic infection and liver disease is still being elucidated. XRN exonucleases can restrict HCV replication and may help to resolve HCV infections. However, it is unknown how 5' triphosphorylated HCV transcripts, primary products of the viral polymerase, become susceptible to attack by 5' monophosphate-specific XRNs. Here, we show that the 5' RNA triphosphatase DUSP11 acts on HCV transcripts, rendering them susceptible to XRN-mediated attack. Cells lacking DUSP11 show substantially enhanced HCV replication, and this effect is diminished when XRN expression is reduced. MicroRNA-122 (miR-122), a target of current phase II anti-HCV drugs, is known to protect HCV transcripts against XRNs. We show that HCV replication is less dependent on miR-122 in cells lacking DUSP11. Combined, these results implicate DUSP11 as an important component of XRN-mediated restriction of HCV.

KEYWORDS:

miR-122; microRNA; restriction factor

PMID:
30038017
PMCID:
PMC6094126
DOI:
10.1073/pnas.1802326115
[Indexed for MEDLINE]
Free PMC Article

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