Hepatitis Delta Virus Large Antigen Sensitizes to TNF-α-Induced NF-κB Signaling

Abstract

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.

Hepatitis delta virus: From biological and medical aspects to current and investigational therapeutic options

“…NF-κB activity has also been shown to be modulated by HDV. Several mechanisms have been proposed, including L-HDAg direct interaction with TRAF-2 and potentiation of TNF-α induced NF-κB transcriptional activation (188), induction of endoplasmic reticulum stress (189), and production of reactive oxygen species upon expression of L-HDAg (190).…”

Hepatitis D Virus Coinfection and Superinfection

“…In addition, HDV seems to sensitize cells to inflammatory stimuli. The large isoform of HDAg increases the tumor necrosis factor (TNF)-a-induced nuclear factor (NF)-kB signaling, probably via a direct interaction with the TNF-receptor-associated factor 2 (TRAF2), a factor involved in early signal transduction (Park et al 2009). More generally, HDV products-encompassing the two HDAg isoforms and the various RNA species-have been shown to interact at several levels with the host cell proteome (Mota et al 2008(Mota et al , 2009), including factors involved in the regulation of cell metabolism and energetic homeostasis, nucleic acid and protein metabolism, and apoptosis and cell growth.…”

Hepatitis D

“…48,49 More intriguing, the participation of HDV in the regulation of cellular gene expression could trigger HDV-related liver damage. The L-HD Ag is sensitive to tumor necrosis factor-α induced NF-κB signaling 50 and isoprenylation of L-HD Ag appears to regulate transforming growth factor-β induced signal transduction; through these mechanisms, the virus might induce liver fibrosis. 51 In the 1980 and 1990s the majority of the patients with chronic hepatitis D in the Mediterranean area were HBsAg carriers superinfected in adolescence or early adulthood, and presented with active cirrhosis at age 40 to 50.…”