title: Hepatitis C virus inhibits interferon signaling through up-regulation of protein phosphatase 2A.
abstract: OBJECTIVE
  To establish a chronic infection, hepatitis C virus (HCV) has to evade the host defense. Expression of HCV proteins in cultured cells and in hepatocytes of transgenic mice inhibits interferon-alpha-induced intracellular signaling through the Jak-STAT (signal transducer and activator of transcription) pathway. It is not known if interferon-alpha signaling is inhibited in patients with chronic hepatitis C as well, and the molecular mechanisms are not well defined.
  
  
  METHODS
  Interferon-alpha-induced signaling was investigated in liver biopsies from patients with chronic hepatitis C. The molecular mechanisms of HCV interference with Jak-STAT signaling were analyzed in cultured cells, HCV transgenic mice, and liver biopsies.
  
  
  RESULTS
  Interferon-alpha-induced DNA binding of STAT1 was significantly impaired in liver biopsies from patients with chronic hepatitis C compared with controls. Tyrosine and serine phosphorylation of STAT1 were intact, but methylation of STAT1 on arginine 31 was reduced. Hypomethylated STAT1 associated with PIAS1, an inhibitor of STAT DNA binding. Increased expression levels of Protein Phosphatase 2A were found in liver extracts from HCV transgenic mice and in liver biopsies of patients with chronic hepatitis C. Overexpression of PP2Ac in Huh7 cells resulted in hypomethylation of STAT1, increased binding to PIAS1, and reduced interferon-alpha-induced DNA binding of STAT1.
  
  
  CONCLUSIONS
  We conclude that HCV interferes with interferon-alpha signaling via up-regulation of PP2Ac, hypomethylation of STAT1, and increased STAT1-PIAS1 association, resulting in reduced transcriptional activation of interferon-alpha-stimulated genes.
authors.affiliation: Department of Research, University Hospital Basel, Basel, Switzerland.
authors.forename: Francois H T
authors.initials: FH
authors.lastname: Duong
authors.forename: Magdalena
authors.initials: M
authors.lastname: Filipowicz
authors.forename: Marco
authors.initials: M
authors.lastname: Tripodi
authors.forename: Nicola
authors.initials: N
authors.lastname: La Monica
authors.forename: Markus H
authors.initials: MH
authors.lastname: Heim
mesh_terms: D000328:Adult; D000368:Aged; D000818:Animals; D000998:Antiviral Agents / Q000494:pharmacology*; D001120:Arginine / Q000378:metabolism; D006528:Carcinoma, Hepatocellular / Q000378:metabolism / Q000473:pathology; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000378:metabolism; D005260:Female; D016174:Hepacivirus / Q000502:physiology*; D019698:Hepatitis C, Chronic / Q000378:metabolism / Q000473:pathology; D006801:Humans; D016898:Interferon-alpha / Q000494:pharmacology*; D007527:Isoenzymes / Q000378:metabolism; D008099:Liver / Q000378:metabolism / Q000473:pathology; D008113:Liver Neoplasms / Q000378:metabolism / Q000473:pathology; D008297:Male; D008745:Methylation; D051379:Mice; D008822:Mice, Transgenic; D008875:Middle Aged; D010749:Phosphoprotein Phosphatases / Q000378:metabolism*; D050828:Protein Inhibitors of Activated STAT; D054648:Protein Phosphatase 2; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D011506:Proteins / Q000378:metabolism; D050794:STAT1 Transcription Factor; D015398:Signal Transduction; D015534:Trans-Activators / Q000378:metabolism; D015854:Up-Regulation
chemical_list: D000998:Antiviral Agents; D004268:DNA-Binding Proteins; D016898:Interferon-alpha; D007527:Isoenzymes; C494211:Pias1 protein, mouse; D050828:Protein Inhibitors of Activated STAT; D011506:Proteins; D050794:STAT1 Transcription Factor; C494079:STAT1 protein, human; C494080:Stat1 protein, mouse; D015534:Trans-Activators; D001120:Arginine; D011505:Protein-Tyrosine Kinases; D010749:Phosphoprotein Phosphatases; D054648:Protein Phosphatase 2