Role of NF-κB and Myc Proteins in Apoptosis Induced by Hepatitis B Virus HBx Protein

Abstract

ABSTRACT Chronic infection with hepatitis B virus (HBV) promotes a high level of liver disease and cancer in humans. The HBV HBx gene encodes a small regulatory protein that is essential for viral replication and is suspected to play a role in viral pathogenesis. HBx stimulates cytoplasmic signal transduction pathways, moderately stimulates a number of transcription factors, including several nuclear factors, and in certain settings sensitizes cells to apoptosis by proapoptotic stimuli, including tumor necrosis factor alpha (TNF-α) and etopocide. Paradoxically, HBx activates members of the NF-κB transcription factor family, some of which are antiapoptotic in function. HBx induces expression of Myc protein family members in certain settings, and Myc can sensitize cells to killing by TNF-α. We therefore examined the roles of NF-κB, c-Myc, and TNF-α in apoptotic killing of cells by HBx. RelA/NF-κB is shown to be induced by HBx and to suppress HBx-mediated apoptosis. HBx also induces c-Rel/NF-κB, which can promote apoptotic cell death in some contexts or block it in others. Induction of c-Rel by HBx was found to inhibit its ability to directly mediate apoptotic killing of cells. Thus, HBx induction of NF-κB family members masks its ability to directly mediate apoptosis, whereas ablation of NF-κB reveals it. Investigation of the role of Myc protein demonstrates that overexpression of Myc is essential for acute sensitization of cells to killing by HBx plus TNF-α. This study therefore defines a specific set of parameters which must be met for HBx to possibly contribute to HBV pathogenesis.