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.

Figure 1

Hepatitis B Virus (HBV) life cycle. See text for details. pgRNA-pre-genomic RNA, cccDNA-covalently closed circular DNA, ER-endoplasmic reticulum.

Figure 2

Various functions of HBx. HBx is known to modulate a number of cellular pathways as shown. Many of these pathways are interlinked and thus only a small number of upstream initiating events might be responsible for invoking a multifaceted response in hepatocytes upon HBx expression.

Figure 3

Potential mechanisms by which HBx induces or inhibits apoptosis in different cells. See text for details.

Figure 4

Localization of HBx to mitochondria results in ROS generation. ROS generation by mitochondria can lead to increased apoptosis due to loss of mitochondrial membrane potential. ROS has also been shown to play an important role in HBx induced activation of cell signaling pathways that have been shown to inhibit apoptosis.