Hepatitis B virus pathogenesis mediated by the HBV HBx protein

The hepatitis B virus X protein (HBx) is a multifunctional regulatory protein that is essential for viral infectivity and has been implicated in virus-mediated liver carcinogenesis and pathogenesis. The role of HBx involved in viral pathogenesis has remained obscure. HBx has been shown to function as a promiscuous transactivator of many viral and cellular promoters, activating transcription factors, such as AP-1 and NF-{dollar}kappa{dollar}B. To understand the molecular mechanism for HBx activity, the induction of NF-{dollar}kappa{dollar}B DNA binding activity and the molecular mechanism by which HBx stimulated NF-{dollar}kappa{dollar}B were investigated. It was found that HBx induces prolonged formation, in a Ras-dependent manner, of transcriptionally active NF-{dollar}kappa{dollar}B DNA-binding complexes, which are composed of the family of Rel proteins, p50, p52, RelA and c-Rel. HBx was found to activate NF-{dollar}kappa{dollar}B through two distinct cytoplasmic pathways by acting on both inhibitor I{dollar}kappa{dollar}B{dollar}alpha{dollar} and p105, the precursor protein of p50.; It has been suggested that persistent infection with hepatitis B virus (HBV) is a leading cause of human liver diseases. Apoptosis is an important mediator of chronic liver diseases caused by HBV infection. It was demonstrated that HBx sensitizes Chang liver cells to TNF{dollar}alpha{dollar}-mediated apoptotic killing when expressed during viral replication in culture cells and in transfected cells independently of other HBV genes. It was next found that HBx induced apoptosis by prolonged stimulation of N-Myc and the stress-mediated mitogen-activated-protein kinase kinase kinase (MEKK) pathway but not by up-regulating TNF receptors. Treatment of cells with a mitogenic growth factor, IGFII, produced by many virus-induced tumors impaired induction of apoptosis by HBx and TNF{dollar}alpha{dollar}, indicating that enhanced apoptotic killing by HBx and TNF{dollar}alpha{dollar} might select for neoplastic hepatocytes that survive by synthesizing mitogenic growth factors.; It was next shown that NF-{dollar}kappa{dollar}B plays a role in controlling apoptosis. HBx was found to induce apoptosis in both wild type and RelA-deficient 3T3 cells, and this apoptotic killing was enhanced by inactivation of RelA/NF-{dollar}kappa{dollar}B, suggesting that RelA/NF-{dollar}kappa{dollar}B may prevent HBx-induced cell death.