Nonstructural 5A protein activates β-catenin signaling cascades: Implication of hepatitis C virus-induced liver pathogenesis

Chul Yong Park, Soo Ho Choi, Sang Min Kang, Ju Il Kang, Byung-Yoon Ahn, Hoguen Kim, Guhung Jung, Kang Yell Choi, Soon B. Hwang

Research output: Contribution to journalArticle

55 Citations (Scopus)

Abstract

Background/Aims: The nonstructural 5A (NS5A) protein of hepatitis C virus (HCV) has been implicated in HCV-induced liver pathogenesis. Wnt/β-catenin signaling has also been involved in tumorigenesis. To elucidate the molecular mechanism of HCV pathogenesis, we examined the potential effects of HCV NS5A protein on Wnt/β-catenin signal transduction cascades. Methods: The effects of NS5A protein on β-catenin signaling cascades in hepatic cells were investigated by luciferase reporter gene assay, confocal microscopy, immunoprecipitation assay, and immunoblot analysis. Results: β-Catenin-mediated transcriptional activity is elevated by NS5A protein, in the context of HCV replication, and by infection of cell culture-produced HCV. NS5A protein directly interacts with endogenous β-catenin and colocalizes with β-catenin in the cytoplasm. NS5A protein inactivates glycogen synthase kinase 3β and increases subsequent accumulation of β-catenin in HepG2 cells. β-Catenin was also accumulated in HCV patients' liver tissues. In addition, the accumulation of β-catenin in HCV replicon cells requires both activation of phosphatidylinositol 3-kinase and inactivation of GSK3β. Conclusions: NS5A activates β-catenin signaling cascades through increasing the stability of β-catenin. This modulation is accomplished by the protein interplay between viral and cellular signaling transducer. These data suggest that NS5A protein may directly be involved in Wnt/β-catenin-mediated liver pathogenesis.

Original languageEnglish
Pages (from-to)853-864
Number of pages12
JournalJournal of Hepatology
Volume51
Issue number5
DOIs
Publication statusPublished - 2009 Nov 1

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Keywords

  • β-Catenin signaling
  • Hepatitis C virus
  • Liver pathogenesis
  • NS5A protein
  • Tumorigenesis

ASJC Scopus subject areas

  • Hepatology

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