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Identification of three interferon-inducible cellular enzymes that inhibit the replication of hepatitis C virus
Journal article   Open access   Peer reviewed

Identification of three interferon-inducible cellular enzymes that inhibit the replication of hepatitis C virus

Dong Jiang, Haitao Guo, Chunxiao Xu, Jinhong Chang, Baohua Gu, Lijuan Wang, Timothy M Block and Ju-Tao Guo
Journal of virology, v 82(4), pp 1665-1678
Feb 2008
DOI: https://doi.org/10.1128/JVI.02113-07
PMID: 18077728
Featured in Collection :   UN Sustainable Development Goals @ Drexel
url
https://doi.org/10.1128/jvi.02113-07View
Published, Version of Record (VoR)Open Access (License Unspecified),  Open

Abstract

Amino Acid Sequence Antiviral Agents - pharmacology Cell Line eIF-2 Kinase - genetics eIF-2 Kinase - metabolism Exonucleases - genetics Exonucleases - metabolism Gene Expression - drug effects Genome, Viral Hepacivirus - drug effects Hepacivirus - physiology Humans Interferon-alpha - pharmacology Molecular Sequence Data Proteins - chemistry Proteins - genetics Proteins - metabolism Replicon - drug effects Replicon - physiology RNA, Viral - genetics S-Adenosylmethionine - metabolism Transfection Virus Replication - drug effects
Hepatitis C virus (HCV) infection is a common cause of chronic hepatitis and is currently treated with alpha interferon (IFN-alpha)-based therapies. However, the underlying mechanism of IFN-alpha therapy remains to be elucidated. To identify the cellular proteins that mediate the antiviral effects of IFN-alpha, we created a HEK293-based cell culture system to inducibly express individual interferon-stimulated genes (ISGs) and determined their antiviral effects against HCV. By screening 29 ISGs that are induced in Huh7 cells by IFN-alpha and/or up-regulated in HCV-infected livers, we discovered that viperin, ISG20, and double-stranded RNA-dependent protein kinase (PKR) noncytolytically inhibited the replication of HCV replicons. Mechanistically, inhibition of HCV replication by ISG20 and PKR depends on their 3'-5' exonuclease and protein kinase activities, respectively. Moreover, our work, for the first time, provides strong evidence suggesting that viperin is a putative radical S-adenosyl-l-methionine (SAM) enzyme. In addition to demonstrating that the antiviral activity of viperin depends on its radical SAM domain, which contains conserved motifs to coordinate [4Fe-4S] cluster and cofactor SAM and is essential for its enzymatic activity, mutagenesis studies also revealed that viperin requires an aromatic amino acid residue at its C terminus for proper antiviral function. Furthermore, although the N-terminal 70 amino acid residues of viperin are not absolutely required, deletion of this region significantly compromises its antiviral activity against HCV. Our findings suggest that viperin represents a novel antiviral pathway that works together with other antiviral proteins, such as ISG20 and PKR, to mediate the IFN response against HCV infection.

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Collaboration types
Domestic collaboration
Web of Science research areas
Virology
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