Hepatitis C Virus Inhibits Interferon Signaling through Up-regulation of Protein Phosphatase 2A

Francois H T Duong, Magdalena Filipowicz, Marco Tripodi, Nicola La Monica, Markus H. Heim

Research output: Contribution to journalArticlepeer-review

Abstract

Background & Aims: 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-α-induced intracellular signaling through the Jak-STAT (signal transducer and activator of transcription) pathway. It is not known if interferon-α signaling is inhibited in patients with chronic hepatitis C as well, and the molecular mechanisms are not well defined. Methods: Interferon-α-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-α-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-α-induced DNA binding of STAT1. Conclusions: We conclude that HCV interferes with interferon-α signaling via up-regulation of PP2Ac, hypomethylation of STAT1, and increased STAT1-PIAS1 association, resulting in reduced transcriptional activation of interferon-α-stimulated genes.

Original languageEnglish
Pages (from-to)263-277
Number of pages15
JournalGastroenterology
Volume126
Issue number1 SUPPL. 1
DOIs
Publication statusPublished - Jan 2004

ASJC Scopus subject areas

  • Gastroenterology

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