Nonstructural 5A protein activates beta-catenin signaling cascades: implication of hepatitis C virus-induced liver pathogenesis.
OBJECTIVE
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 3beta 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 GSK3beta.


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.
Park
Chul-Yong
CY
National Research Laboratory of Hepatitis C Virus and Ilsong Institute of Life Science, Hallym University, Dongan-gu, Anyang, Republic of Korea.
Choi
Soo-Ho
SH
Kang
Sang-Min
SM
Kang
Ju-Il
JI
Ahn
Byung-Yoon
BY
Kim
Hoguen
H
Jung
Guhung
G
Choi
Kang-Yell
KY
Hwang
Soon B
SB
D000818:Animals; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / Q000378:metabolism; D019556:COS Cells; D006528:Carcinoma, Hepatocellular / Q000209:etiology / Q000378:metabolism / Q000821:virology; D002460:Cell Line; D002467:Cell Nucleus / Q000378:metabolism; D002522:Chlorocebus aethiops; D003600:Cytosol / Q000378:metabolism; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D016174:Hepacivirus / Q000235:genetics / Q000472:pathogenicity* / Q000502:physiology*; D006801:Humans; D066298:In Vitro Techniques; D008113:Liver Neoplasms / Q000209:etiology* / Q000378:metabolism / Q000821:virology; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D054730:Protein Interaction Domains and Motifs; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism; D012093:Replicon; D017384:Sequence Deletion; D015398:Signal Transduction; D000073940:Transcription Factor 4; D014157:Transcription Factors / Q000378:metabolism; D014162:Transfection; D017361:Viral Nonstructural Proteins / Q000235:genetics / Q000378:metabolism*; D014779:Virus Replication; D051153:Wnt Proteins / Q000378:metabolism; D051176:beta Catenin / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D012324:RNA-Dependent RNA Polymerase
D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; D038362:Glycogen Synthase Kinase 3; D000071679:Glycogen Synthase Kinase 3 beta; D019869:Phosphatidylinositol 3-Kinases; D011994:Recombinant Proteins; D000073940:Transcription Factor 4; D014157:Transcription Factors; D017361:Viral Nonstructural Proteins; D051153:Wnt Proteins; D051176:beta Catenin; C495270:CTNNB1 protein, human; C532096:TCF4 protein, human; C000605506:GSK3B protein, human; C087036:NS-5 protein, hepatitis C virus; D012324:RNA-Dependent RNA Polymerase