Hepatitis delta virus large antigen sensitizes to TNF-alpha-induced NF-kappaB signaling.
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 viral proteins, the small hepatitis delta antigen (SHDAg) and the large hepatitis delta antigen (LHDAg), on NF-kappaB signaling pathway. In this study, we demonstrated that TNF-alpha-induced NF-kappaB transcriptional activation was increased by LHDAg but not by SHDAg in both HEK293 and Huh7 cells. Furthermore, LHDAg promoted TRAF2-induced NF-kappaB activation. Using coimmunoprecipitation assays, we demonstrated that both SHDAg and LHDAg interacted with TRAF2 protein. We showed that isoprenylation of LHDAg was not required for the increase of NF-kappaB activity. We further showed that only LHDAg but not SHDAg increased the TNF-alpha-mediated nuclear translocation of p65. This was accomplished by activation of IkappaBalpha degradation by LHDAg. Finally, we demonstrated that LHDAg augmented the COX-2 expression level in Huh7 cells. These data suggest that LHDAg modulates NF-kappaB signaling pathway and may contribute to HDV pathogenesis.
Park
Chul-Yong
CY
Ilsong Institute of Life Science, Hallym University, Anyang 431-060, Korea.
Oh
Sang-Heun
SH
Kang
Sang Min
SM
Lim
Yun-Sook
YS
Hwang
Soon B
SB
D002460:Cell Line; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000378:metabolism; D051546:Cyclooxygenase 2 / Q000235:genetics / Q000378:metabolism; D015870:Gene Expression; D006367:HeLa Cells; D035923:Hepatitis delta Antigens / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D015151:Immunoblotting; D008156:Luciferases / Q000235:genetics / Q000378:metabolism; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism*; D011485:Protein Binding; D021381:Protein Transport; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000235:genetics*; D047992:TNF Receptor-Associated Factor 2 / Q000235:genetics / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*
D035923:Hepatitis delta Antigens; D016328:NF-kappa B; D011993:Recombinant Fusion Proteins; D047992:TNF Receptor-Associated Factor 2; D014409:Tumor Necrosis Factor-alpha; C442244:hepatitis delta virus large antigen; D008156:Luciferases; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human