Modulation of Apoptotic Signaling by the Hepatitis B Virus X Protein

Abstract

Worldwide, an estimated 350 million people are chronically infected with the Hepatitis B Virus (HBV); chronic infection with HBV is associated with the development of severe liver diseases including hepatitis and cirrhosis. Individuals who are chronically infected with HBV also have a significantly higher risk of developing hepatocellular carcinoma (HCC) than uninfected individuals. The HBV X protein (HBx) is a key regulatory HBV protein that is important for HBV replication, and likely plays a cofactor role in the development of HCC in chronically HBV-infected individuals. Although some of the functions of HBx that may contribute to the development of HCC have been characterized, many HBx activities, and their putative roles during the development of HBV-associated HCC, remain incompletely understood. HBx is a multifunctional protein that localizes to the cytoplasm, nucleus, and mitochondria of HBV‑infected hepatocytes. HBx regulates numerous cellular signal transduction pathways and transcription factors as well as cell cycle progression and apoptosis. In this review, we will summarize reports in which the impact of HBx expression on cellular apoptotic pathways has been analyzed. Although various effects of HBx on apoptotic pathways have been observed in different model systems, studies of HBx activities in biologically relevant hepatocyte systems have begun to clarify apoptotic effects of HBx and suggest mechanisms that could link HBx modulation of apoptotic pathways to the development of HBV-associated HCC.

The Hepatitis B Virus (HBV) HBx Protein Activates AKT To Simultaneously Regulate HBV Replication and Hepatocyte Survival

“…The regulation of HBV replication by various cell signal transduction pathways has been studied mostly with immortalized or transformed cell lines, and the results of many of these studies suggest that some HBx activities may be cell context dependent. Therefore, the results of studies conducted with immortalized or transformed cell lines may or may not be relevant to HBx activities in normal hepatocytes and the associated effects on HBV replication (11,44). Cultured primary rat and human hepatocytes are Primary rat hepatocytes were transfected and treated as described above for panel A, and Western blot analysis was performed to check the levels of cleaved caspase-3.…”

“…While studies conducted with various cell lines have provided important insights concerning the effect of HBx expression on cellular signal transduction pathways, the influence of HBx expression on cellular signal transduction pathways in normal hepatocytes, and in the context of an HBV infection, remains poorly understood. Recent studies with ex vivo-cultured primary hepatocyte model systems and in vivo models have begun to identify HBx effects on normal hepatocytes and how these HBx activities influence HBV replication and affect hepatocyte physiology (8,11,14,23,26,27).…”

“…HBx is also thought to play an important role in the development of HBV-associated HCC due to the regulatory effects of HBx on cellular signaling pathways, DNA damage repair mechanisms, the cell cycle, and apoptosis (14,(20)(21)(22)(23)(24). Some HBx activities, such as its role in regulating apoptosis, appear to be context dependent and have varied depending upon the model system that was used to assess this HBx activity (8,11,25). While studies conducted with various cell lines have provided important insights concerning the effect of HBx expression on cellular signal transduction pathways, the influence of HBx expression on cellular signal transduction pathways in normal hepatocytes, and in the context of an HBV infection, remains poorly understood.…”

“…The shortest open reading frame (ORF) and mRNA transcript of the HBV genome encodes the HBx protein (11,13). HBx stimulates HBV replication in multiple experimental systems, including cultured primary rat and human hepatocytes, some liver cell lines, livers of normal mice, and chimeric mice with humanized livers (14)(15)(16)(17)(18)(19).…”

“…Pregenomic RNA (pgRNA), one of the longest HBV transcripts, is enclosed in capsids; pgRNA is covalently linked to the viral DNA polymerase/reverse transcriptase (RT), which reverse transcribes the first DNA strand of the HBV genome by using pgRNA as the template. For reasons that remain incompletely understood, the second, cDNA strand is synthesized to various lengths, giving rise to the partially double-stranded genome of HBV (9)(10)(11). The interaction between numerous host cell factors and HBV proteins governs HBV replication in hepatocytes and likely plays an important role in the development of HBVassociated HCC (3,8,11,12).…”