The hepatitis C viral nonstructural protein 5A stabilizes growth-regulatory human transcripts

Liang Guo, Suresh D. Sharma, Jose Debes, Daniel Beisang, Bernd Rattenbacher, Irina Vlasova St Louis, Darin L. Wiesner, Craig E. Cameron, Paul R. Bohjanen

Research output: Contribution to journalArticlepeer-review

3 Scopus citations

Abstract

Numerous mammalian proto-oncogene and other growth-regulatory transcripts are upregulated in malignancy due to abnormal mRNA stabilization. In hepatoma cells expressing a hepatitis C virus (HCV) subgenomic replicon, we found that the viral nonstructural protein 5A (NS5A), a protein known to bind to viral RNA, also bound specifically to human cellular transcripts that encode regulators of cell growth and apoptosis, and this binding correlated with transcript stabilization. An important subset of human NS5A-target transcripts contained GU-rich elements, sequences known to destabilize mRNA. We found that NS5A bound to GU-rich elements in vitro and in cells. Mutation of the NS5A zinc finger abrogated its GU-rich element-binding and mRNA stabilizing activities. Overall, we identified a molecular mechanism whereby HCV manipulates host gene expression by stabilizing host transcripts in a manner that would promote growth and prevent death of virus-infected cells, allowing the virus to establish chronic infection and lead to the development of hepatocellular carcinoma.

Original languageEnglish (US)
Pages (from-to)2537-2547
Number of pages11
JournalNucleic acids research
Volume46
Issue number5
DOIs
StatePublished - Mar 16 2018

Bibliographical note

Funding Information:
National Institutes of Health (NIH) [AI057484, AI072068 to P.R.B., AI053531 to C.E.C., T32 AI83196 to L.G.]; Swiss National Science Foundation (to B.R.); Lymphoma Research Foundation and start-up funds from the Department of Medicine at the University of Minnesota (to I.V.-S.). Funding for open access charge: University of Minnesota Institutional Funds. Conflict of interest statement. None declared.

Funding Information:
We thank Dr Ibrahim Moustafa for preparing Figure 5A and Dr Ann-Bin Shyu for providing plasmids. The University of Minnesota Supercomputing Institute provided the access to Ingenuity Pathway Assistant (Qiagen Inc). None of the authors has a conflict of interest. National Institutes of Health (NIH) [AI057484, AI072068 to P.R.B., AI053531 to C.E.C., T32 AI83196 to L.G.]; Swiss National Science Foundation (to B.R.); Lymphoma Research Foundation and start-up funds from the Department of Medicine at the University of Minnesota (to I.V.-S.). Funding for open access charge: University of Minnesota Institutional Funds.

Publisher Copyright:
© The Author(s) 2018. Published by Oxford University Press on behalf of Nucleic Acids Research.

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