Nonstructural 5A protein activates beta-catenin signaling cascades: Implication of hepatitis C virus-induced liver pathogenesis
- 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.
- Issue Date
- 11월-2009
- Publisher
- ELSEVIER SCIENCE BV
- Keywords
- Hepatitis C virus; Liver pathogenesis; NS5A protein; beta-Catenin signaling; Tumorigenesis
- Citation
- JOURNAL OF HEPATOLOGY, v.51, no.5, pp.853 - 864
- Indexed
- SCIE
SCOPUS
- Journal Title
- JOURNAL OF HEPATOLOGY
- Volume
- 51
- Number
- 5
- Start Page
- 853
- End Page
- 864
- URI
- https://scholar.korea.ac.kr/handle/2021.sw.korea/118956
- DOI
- 10.1016/j.jhep.2009.06.026
- ISSN
- 0168-8278
- Abstract
- Background/Aims: The nonstructural 5A (NS5A) protein of hepatitis C virus (HCV) has been implicated in HCV-induced liver pathogenesis. Wnt/beta-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/beta-catenin signal transduction cascades. Methods:The effects of NS5A protein on beta-catenin signaling cascades in hepatic cells were investigated by luciferase reporter gene assay, confocal microscopy, immunoprecipitation assay, and immunoblot analysis. Results: beta-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 beta-catenin and colocalizes with beta-catenin in the cytoplasm. NS5A protein inactivates glycogen synthase kinase 3 beta and increases subsequent accumulation of beta-catenin in HepG2 cells. beta-Catenin was also accumulated in HCV patients' liver tissues. In addition, the accumulation of beta-catenin in HCV replicon cells requires both activation of phosphatidylinositol 3-kinase and inactivation of GSK3 beta. Conclusions: NS5A activates beta-catenin signaling cascades through increasing the stability of beta-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/beta-catenin-mediated liver pathogenesis. (C) 2009 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.
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