IFN-alpha antagonistic activity of HCV core protein involves induction of suppressor of cytokine signaling-3.
Eighty percent of patients newly infected with the hepatitis C virus (HCV) develop chronic infection, suggesting that HCV can develop effective strategies to escape the unspecific and specific immune response of the host. Because SOCS molecules have been recognized to be powerful inhibitors of cytokine signaling via the Jak/STAT pathway, virus-induced expression of these molecules should be an efficient instrument to counteract the cellular response toward interferons (IFNs), an essential part of first line antiviral immune response. This study shows that overexpression of HCV core protein inhibits IFN-alpha-induced tyrosine phosphorylation and activation of STAT1 in hepatic cells. With the use of a STAT1-YFP fusion protein, further evidence is given that HCV core is capable to inhibit nuclear translocation of STAT1. Inhibition of STAT1-tyrosine phosphorylation was accompanied by the induction of SOCS3-mRNA expression, suggesting that the HCV core protein impairs IFN-alpha-induced signal transduction via induction of SOCS3 expression. HCV core protein was competent to partially rescue growth of a genetically engineered influenza A virus lacking its own IFN antagonist. These IFN-antagonistic properties of the HCV core protein may be part of the molecular basis of IFN-alpha unresponsiveness in about one-half of chronically infected HCV-patients.
Bode
Johannes G
JG
Klinik für Gastroenterologie, Hepatologie und Infektiologie, Medizinische Klinik der Heinrich-Heine Universität, 40255 Düsseldorf, Germany. Johannes.Bode@t-online.de
Ludwig
Stephan
S
Ehrhardt
Christina
C
Albrecht
Ute
U
Erhardt
Andreas
A
Schaper
Fred
F
Heinrich
Peter C
PC
Häussinger
Dieter
D
D021581:Active Transport, Cell Nucleus; D002460:Cell Line; D002467:Cell Nucleus / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism; D006801:Humans; D009980:Influenza A virus / Q000235:genetics / Q000254:growth & development; D016898:Interferon-alpha / Q000037:antagonists & inhibitors*; D008954:Models, Biological; D014176:Protein Biosynthesis; D011506:Proteins / Q000235:genetics; D012097:Repressor Proteins; D050794:STAT1 Transcription Factor; D015398:Signal Transduction; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D015534:Trans-Activators / Q000378:metabolism; D014157:Transcription Factors; D015533:Transcriptional Activation; D014162:Transfection; D014758:Viral Core Proteins / Q000235:genetics*
D004268:DNA-Binding Proteins; D016898:Interferon-alpha; D011506:Proteins; D012097:Repressor Proteins; C106644:SOCS3 protein, human; D050794:STAT1 Transcription Factor; C494079:STAT1 protein, human; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D015534:Trans-Activators; D014157:Transcription Factors; D014758:Viral Core Proteins; C069130:nucleocapsid protein, Hepatitis C virus