The hepatitis C viral nonstructural protein 5A stabilizes growth-regulatory human transcripts
Liang Guo1,2,3, Suresh D Sharma4, Jose D Debes1
1Department of Medicine, Division of Infectious Diseases and International Medicine, Program in Infection and Immunity, University of Minnesota, Minneapolis, MN 55455, USA.
Nucleic Acids Research
|February 1, 2018
Summary
Hepatitis C virus (HCV) protein NS5A stabilizes human cellular transcripts, promoting cell growth and survival. This mechanism helps the virus establish chronic infection and potentially leads to liver cancer.
Area of Science:
- Molecular biology
- Virology
- Oncology
Background:
- Malignancy often involves upregulation of growth-regulatory transcripts due to abnormal mRNA stabilization.
- Hepatocellular carcinoma (HCC) is a significant global health concern linked to chronic infections like Hepatitis C virus (HCV).
Purpose of the Study:
- To investigate the molecular mechanism by which HCV nonstructural protein 5A (NS5A) influences host gene expression.
- To determine if NS5A binding to cellular transcripts contributes to mRNA stabilization and promotes cell survival in infected cells.
Main Methods:
- Hepatoma cells expressing an HCV subgenomic replicon were used.
- NS5A protein's binding to human cellular transcripts was analyzed.
- In vitro and cellular assays were performed to study NS5A binding to GU-rich elements.
- Mutational analysis of the NS5A zinc finger domain was conducted.
Main Results:
- HCV NS5A specifically bound to human cellular transcripts regulating cell growth and apoptosis.
- NS5A binding correlated with the stabilization of these target transcripts.
- NS5A was found to bind to GU-rich elements, which are typically mRNA destabilizing sequences.
- Mutation of the NS5A zinc finger domain abolished its RNA-binding and mRNA-stabilizing activities.
Conclusions:
- HCV NS5A manipulates host gene expression by stabilizing cellular transcripts that promote cell growth and inhibit apoptosis.
- This viral strategy facilitates chronic HCV infection and contributes to the development of hepatocellular carcinoma.
- Targeting NS5A-RNA interactions could offer a novel therapeutic strategy against HCV-induced liver cancer.
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