Effects of the hepatitis C virus core protein on innate cellular defense pathways.
The hepatitis C virus (HCV) core protein is thought to contribute to HCV pathogenesis through its interaction with various signal transduction pathways. In this study, we explored the interaction of the core protein with innate defense pathways (interferon [IFN] regulatory factor [IRF], Jak-Stat, and inducible nitric oxide synthase [iNOS]) in HeLa and Huh7 human cell lines. Expression of a patient-derived genotype 1b core protein activated human IRF-1 and guanylate-binding protein-2 (GBP-2) promoters, induced IRF-1 mRNA, but failed to induce IRF-3 phosphorylation. HCV core protein caused dose-dependent induction of the IFN-beta promoter and IFN-beta mRNA but not the IFN-alpha1 and IFN-alpha4 promoters. In the presence of IFN-alpha, core expression was associated with increased IFN-stimulated gene factor 3 (ISGF3) binding to the IFN-stimulated response element (ISRE) and tyrosine phosphorylation of Stat1. Core expression resulted in dose-dependent activation of the ISRE and gamma activated sequence (GAS) promoters, in both the absence and the presence of either IFN-alpha or IFN-gamma. Core stimulated the human iNOS promoter and induced iNOS protein. The data indicate that HCV core can modulate IRF, Jak-Stat, and iNOS pathways and suggest mechanisms by which core could affect HCV persistence and pathogenesis.
Virology Division, Department of Laboratory Medicine, University of Washington, Seattle, WA 98104-2499, USA.
Kristen
K
Miller
Susan
S
McArdle
Michael J
MJ
Gale
David A
DA
Geller
Benjamin
B
Tenoever
John
J
Hiscott
David R
DR
Gretch
Stephen J
SJ
Polyak
D004268:DNA-Binding Proteins / Q000096:biosynthesis / Q000235:genetics; D006367:HeLa Cells; D016174:Hepacivirus / Q000235:genetics / Q000378:metabolism / Q000472:pathogenicity*; D006801:Humans; D007113:Immunity, Innate; D050856:Interferon Regulatory Factor-1; D016898:Interferon-alpha / Q000096:biosynthesis / Q000235:genetics; D016899:Interferon-beta / Q000096:biosynthesis / Q000235:genetics; D019001:Nitric Oxide Synthase / Q000096:biosynthesis / Q000235:genetics; D052247:Nitric Oxide Synthase Type II; D010750:Phosphoproteins / Q000096:biosynthesis / Q000235:genetics; D011401:Promoter Regions, Genetic / Q000235:genetics; D015398:Signal Transduction; D014157:Transcription Factors / Q000096:biosynthesis / Q000235:genetics; D014758:Viral Core Proteins / Q000235:genetics
D004268:DNA-Binding Proteins; C494257:IRF1 protein, human; D050856:Interferon Regulatory Factor-1; D016898:Interferon-alpha; D010750:Phosphoproteins; D014157:Transcription Factors; D014758:Viral Core Proteins; C069130:nucleocapsid protein, Hepatitis C virus; D016899:Interferon-beta; C496319:NOS2 protein, human; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II