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

• Published in: Journal of hepatology 2009-11, Vol.51 (5), p.853-864
• Main Authors: Park, Chul-Yong, Choi, Soo-Ho, Kang, Sang-Min, Kang, Ju-Il, Ahn, Byung-Yoon, Kim, Hoguen, Jung, Guhung, Choi, Kang-Yell, Hwang, Soon B
• Format: Article
• Language: English
• Subjects: Animals; Basic Helix-Loop-Helix Leucine Zipper Transcription Factors - metabolism; beta Catenin - chemistry; beta Catenin - genetics; beta Catenin - metabolism; Biological and medical sciences; Carcinoma, Hepatocellular - etiology; Carcinoma, Hepatocellular - metabolism; Carcinoma, Hepatocellular - virology; Cell Line; Cell Nucleus - metabolism; Chlorocebus aethiops; COS Cells; Cytosol - metabolism; Gastroenterology and Hepatology; Gastroenterology. Liver. Pancreas. Abdomen; Glycogen Synthase Kinase 3 - antagonists & inhibitors; Glycogen Synthase Kinase 3 - metabolism; Glycogen Synthase Kinase 3 beta; Hepacivirus - genetics; Hepacivirus - pathogenicity; Hepacivirus - physiology; Hepatitis C virus; Humans; In Vitro Techniques; Liver Neoplasms - etiology; Liver Neoplasms - metabolism; Liver Neoplasms - virology; Liver pathogenesis; Medical sciences; NS5A protein; Phosphatidylinositol 3-Kinases - metabolism; Protein Interaction Domains and Motifs; Recombinant Proteins - genetics; Recombinant Proteins - metabolism; Replicon; Sequence Deletion; Signal Transduction; Transcription Factor 4; Transcription Factors - metabolism; Transfection; Tumorigenesis; Viral Nonstructural Proteins - genetics; Viral Nonstructural Proteins - metabolism; Virus Replication; Wnt Proteins - metabolism; β-Catenin signaling
• ISSN: 0168-8278; 1600-0641
• DOI: 10.1016/j.jhep.2009.06.026

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.