Hepatitis delta virus large antigen sensitizes to TNF-α-induced NF-κB 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-kappa B signaling pathway. In this study, we demonstrated that TNF-alpha-induced NF-kappa B transcriptional activation was increased by LHDAg but not by SHDAg in both HEK293 and Huh7 cells. Furthermore, LHDAg promoted TRAF2-induced NF-kappa B 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-kappa B 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 I kappa B alpha degradation by LHDAg. Finally, we demonstrated that LHDAg augmented the COX-2 expression level in Huh7 cells. These data suggest that LHDAg modulates NF-kappa B signaling pathway and may contribute to HDV pathogenesis.