Article
Viperin: a multifunctional, interferon-inducible protein that regulates virus replication.
Department of Immunobiology, Yale University School of Medicine New Haven, CT 06520-8011, USA.
Cell host & microbe (impact factor:
13.02).
12/2011;
10(6):534-9.
DOI:10.1016/j.chom.2011.11.004
pp.534-9
Source: PubMed
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Article: Identification of three interferon-inducible cellular enzymes that inhibit the replication of hepatitis C virus.
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ABSTRACT: 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.Journal of Virology 03/2008; 82(4):1665-78. · 5.40 Impact Factor
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Keywords
cellular metabolic pathways
current status
human cytomegalovirus
interferon-inducible protein
intracellular signaling pathways
viruses
