Hepatitis B X Protein
The smallest ORF in the HBV
genome encodes for the hepatitis B X protein (HBx). HBx is aptly named
as its entire function and cellular localization remain a mystery. This
154 amino acid protein has conserved sequences between human, woodchuck,
and ground squirrel hepadnaviruses. However, avian hepadnaviruses lack
HBx. As such, HBx is not believed to be involved directly in genomic replication
or viral assembly.
HBx has not been found in mature virions nor associated with nucleocapsid particles. Sequence analysis suggests that HBx is localized in the cytoplasm. HBx can be phosphorylated. (1) However, studies on HBx have been hampered by its apparent rapid turnover when expressed in vitro. (2)
A plethora of functions have been assigned to HBx. Some suggest that HBx has serine/threonine kinase activity (3) while others report the ability of HBx to upregulate the transcription of many endogenous host genes. HBx is thought to enhance the DNA binding ability of other transcription factors through interaction with their leucine zipper regions (bZip). (4)
Perhaps the most intriguing effect HBx may have on HBV infected cells is its tumorigenic activity. Overexpression of HBx in hepatocyte cultures and transgenic mice results in a tumorigenic phenotype. (5), (6) Some evidence suggest that HBx interacts with the ras-raf-MAP kinase pathway to promote cell growth and activity. (7) HBx is also implicated in regulating Sp1 mediated transcription of an insulin-like growth factor II (IGF-II). (8) Moreover, HBx has been shown to bind onto p53, a prominent cell tumour-suppressor protein. (9)
However, HBx is not easily detected in hepatocarcinoma (HCC) tissues nor in active HBV infected cells. Though many functions have been associated with HBx, their validity remains in question simply due to the levels of HBx seen in infected cells. As such, the nature and purpose of the HBx protein remains to be characterized.
References:
1.
Schek, N., Bartenschlager, R., Kuhn, C. and Schaller, H. 1991. Phosphorylation
and Rapid Turnover of Hepatitis B Virus X-Protein Expressed in HepG2 Cells
from a Recombinant Vaccinia Virus. Oncogene; 6: 1735-1744.
2. Schek, N., Bartenschlager, R., Kuhn, C. and Schaller, H. 1991. Phosphorylation and Rapid Turnover of Hepatitis B Virus X-Protein Expressed in HepG2 Cells from a Recombinant Vaccinia Virus. Oncogene; 6: 1735-1744.
3. Wu, J.Y., Zhou,Z.Y., Judd, A., Cartwright, C.A. and Robinson, W.S. 1990. The Hepatitis B Virus-Encoded Transcriptional Transactivator HBx Appears to be a Novel Protein Serine/Threonine Kinase. Cell; 63: 687-695.
4. Barnabas, S., Hai, T. and Adrisani, O.M. 1997. The Hepatitis B Virus X Protein Enhances the DNA Binding Potential and Transcription Efficacy of bZip Transcription Factors. J Biol Chem; 272(33): 20684-20690.
5. Seifer, M., Hohne, M., Schaefer, S. and Gerlich, W.S. 1992. In vitro Tumorigenicity of Hepatitis B Virus DNA and HBx Protein. J Hepatology; 13 (suppl. 4): S61-S65.
6. Kim, C.M., Koike, K., Saito, I., Miyamura, T. and Jay, G. 1991. HBx Gene of Hepatitis B Virus Induces Liver Cancer in Transgenic Mice. Nature; 351: 317-320.
7. Wang, H.D., Trivedi, A., and Johnson, D.L. 1997. Hepatitis B Virus X Protein Induces RNA Polymerase III-Dependent Gene Transcription and Increases Cellular TATA-Binding Protein by Activating the Ras Signalling Pathway. Mol Cell Biol; 17(12): 6838-6846.
8. Lee, Y.I., Lee, S., Lee, Y., Bong, Y.S., Hyun, S.W., Yoo, Y.D., Kim, S.J., Kim, Y.W. and Poo, H.R. 1998. The Human Hepatitis B Virus Transactivator X Gene Product Regulates Sp1 Mediated Transcription of an Insulin-Like Growth Factor II Promoter 4. Oncogene; 16: 2367-2380.
9. Feitelson et al., 1993.
