Large hepatitis delta antigen modulates transforming growth factor-beta signaling cascades: implication of hepatitis delta virus-induced liver fibrosis.
OBJECTIVE
Transforming growth factor-beta (TGF-beta) has been implicated in the pathogenesis of liver disease. TGF-beta is involved in liver regeneration and in the fibrotic and cirrhotic transformation with hepatitis viral infection. Hepatitis delta virus (HDV) infection causes fulminant hepatitis and liver cirrhosis. To elucidate the molecular mechanism of HDV pathogenesis, we examined the effects of HDV-encoded-only protein, the small hepatitis delta antigen (SHDAg), and the large hepatitis delta antigen (LHDAg), on TGF-beta- and c-Jun-induced signaling cascades.


METHODS
The effects of either SHDAg or LHDAg on TGF-beta- and c-Jun-induced signaling cascades in Huh7 and Cos7 cells were investigated by luciferase reporter gene assay, immunoprecipitation assay, electrophoretic mobility shift assay, Western blot analysis, and confocal microscopy analysis.


RESULTS
The LHDAg, but not the SHDAg, potentiated TGF-beta- and c-Jun-induced signal activation, and the isoprenylation of LHDAg played a major role in signaling cascades. LHDAg synergistically activated hepatitis B virus X protein-mediated TGF-beta and AP-1 signaling cascades. In addition, LHDAg enhanced the protein expression level of TGF-beta-induced plasminogen activator inhibitor-1.


CONCLUSIONS
LHDAg may induce liver fibrosis through the regulation of TGF-beta-induced signal transductions. This regulation of TGF-beta-mediated signaling is accomplished by the isoprenylation of LHDAg, which is a novel mechanism involved in HDV pathogenesis.
Choi
Soo-Ho
SH
Ilsong Institute of Life Science, Hallym University, 1605-4 Gwanyang-dong, Dongan-gu, Anyang 431-060, Korea.
Jeong
Sook-Hyang
SH
Hwang
Soon B
SB
D000818:Animals; D019556:COS Cells; D045744:Cell Line, Tumor; D002522:Chlorocebus aethiops; D003699:Hepatitis D / Q000378:metabolism* / Q000821:virology; D003698:Hepatitis Delta Virus / Q000235:genetics*; D035923:Hepatitis delta Antigens / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D008103:Liver Cirrhosis / Q000378:metabolism* / Q000821:virology; D008113:Liver Neoplasms; D017395:Plasminogen Activator Inhibitor 1 / Q000378:metabolism; D017368:Protein Prenylation; D017434:Protein Structure, Tertiary; D015398:Signal Transduction / Q000502:physiology*; D051900:Smad3 Protein / Q000737:chemistry / Q000378:metabolism; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism; D018808:Transcription Factor AP-1 / Q000378:metabolism; D014158:Transcription, Genetic / Q000502:physiology; D014162:Transfection; D016212:Transforming Growth Factor beta / Q000378:metabolism*; D054334:Viral Regulatory and Accessory Proteins
D035923:Hepatitis delta Antigens; D017395:Plasminogen Activator Inhibitor 1; C497790:SMAD3 protein, human; D051900:Smad3 Protein; D015534:Trans-Activators; D018808:Transcription Factor AP-1; D016212:Transforming Growth Factor beta; D054334:Viral Regulatory and Accessory Proteins; C057628:hepatitis B virus X protein; C442244:hepatitis delta virus large antigen; D048031:JNK Mitogen-Activated Protein Kinases