Skip to main content
SpringerLink
Log in

Hepadnaviral X protein: Review of recent progress

  • Review
  • Published:
Journal of Biomedical Science

Abstract

In addition to coding for virion structural proteins and the reverse tanscriptase, all mammalian hepadnaviruses also contain an open-reading frame called X, because its function could not be fathomed from the deduced amino acid sequence. While it is now known that the woodchuck virus (and presumably the other hepadnaviruses, as well) cannot replicate in the animal host if the X gene is mutated, the exact function of the X protein in the viral life cycle is still unknown. In transient transfection studies, X protein has been shown to trans-activate a wide variety of promoters. The mechanism of this activation is also unclear, although there is accumulating evidence in favor of both a cytoplasmic effect involving signal transduction pathways, and a nuclear effect directly on the transcriptional machinery. It appears that the X protein is at least as complex as many of the other, better studied viral trans-activators, and may well yield new insights into mammalian cell functions in the future.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Similar content being viewed by others

References

  1. Antunovic J, Lemieux N, Cromlish JA. The 17 kDa HBx protein encoded by hepatitis B virus interacts with the activation domains of Oct-1, and functions as a coactivator in the activation and repression of a human U6 promoter. Cell Mol Biol Res 39:463–482;1993.

    Google Scholar 

  2. Arii M, Takada S, Koike K. Identification of three essential regions of hepatitis B virus X protein for trans-activation function. Oncogene 7:397–403;1992.

    Google Scholar 

  3. Aufiero B, Schneider RJ. The hepatitis B virus X-gene product trans-activates both RNA polymerase II and III promoters. Embo J 9:497–504;1990.

    Google Scholar 

  4. Balsano C, Avantaggiati ML, Natoli G, De Me, Will H, Perricaudet M, Levrero M. Full-length and truncated versions of the hepatitis B virus (HBV) X protein (pX) transactivate the cmyc protooncogene at the transcriptional level. Biochem Biophys Res Commun 176:985–992;1991.

    Google Scholar 

  5. Balsano C, Billet O, Bennoun M, Cavard C, Zider A, Grimber G, Natoli G, Briand P, Levrero M. Hepatitis B virus X gene product acts as a transactivator in vivo. J Hepatol 21:103–109;1994.

    Google Scholar 

  6. Benn J, Schneider RJ. Hepatitis B virus HBx protein activates Ras-GTP complex formation and establishes a Ras, Raf, MAP kinase signaling cascade. Proc Natl Acad Sci USA 91:10350–10354;1994.

    Google Scholar 

  7. Benn J, Schneider RJ. Hepatitis B virus HBx protein deregulates cell cycle checkpoint controls. Proc Natl Acad Sci USA (in press); 1995.

  8. Blum HE, Zhang ZS, Galun E, von Weiszäcker WF, Garner B, Liang TJ, Wands JR. Hepatitis B virus X protein is not central to the viral life cycle in vitro. J Virol 66:1223–1227;1992.

    Google Scholar 

  9. Bressac B, Kew M, Wands J, Ozturk M. Selective G to T mutations of p53 gene in hepatocellular carcinoma from southern Africa. Nature 350:429–431;1991.

    Google Scholar 

  10. Chen HS, Kaneko S, Girones R, Anderson RW, Hornbuckle WE, Tennant BC, Cote PJ, Gerin JL, Purcell RH, Miller RH. The wood-chuck hepatitis virus X gene is important for establishment of virus infection in wood-chucks. J Virol 67:1218–1226:1993.

    Google Scholar 

  11. Cheong JH, Yi M, Lin Y, Murakami S. Human RPB5, a subunit shared by eukaryotic nuclear RNA polymerases, binds human hepatitis B virus X protein and may play a role in X transactivation. EMBO J 14:142–150;1995.

    Google Scholar 

  12. Colgrove R, Simon G, Ganem D. Transcriptional activation of homologous and heterologous genes by the hepatitis B virus X gene product in cells permissive for viral replication. J Virol 63:4019–4026;1989.

    Google Scholar 

  13. Cross JC, Wen P, Rutter WJ. Transactivation by hepatitis B virus X protein is promiscuous and dependent on mitogen-activated cellular serine/threonine kinases. Proc Natl Acad Sci USA 90:8078–8082;1193.

    Google Scholar 

  14. De Medina T, Shaul Y. Functional and structural similarity between the X protein of hepatitis B virus and nucleoside diphosphate kinases. FEBS Lett 351:423–426;1994.

    Google Scholar 

  15. De Medina T, Haviv I, Noiman S, Shaul Y. The X protein of hepatitis B virus has a ribo/deoxy ATPase activity. Virology 202:401–407;1994.

    Google Scholar 

  16. Doria M, Klein N, Lucito R, Schneider RJ. The hepatitis B virus HBx protein is a dual specificity cytoplasmic activator of Ras and nuclear activator of transcription factors. EMBO J (in press); 1995.

  17. Faktor O, Shaul Y. The identification of hepatitis B virus X gene responsive elements reveals functional similarity of X and HTLV-I tax. Oncogene 5:867–872;1990.

    Google Scholar 

  18. Feitelson MA, Zhu M, Duan LX, London WT. Hepatitis B x antigen and p53 are associated in vitro and in liver tissues from patients with primary hepatocellular carcinoma. Oncogene 8:1109–1117;1993.

    Google Scholar 

  19. Fischer M, Runkel L, Schaller H. HBx protein of hepatitis B virus interacts with the C-terminal portion of a novel human proteasome alpha-subunit. Virus Genes 10:99–102;1995.

    Google Scholar 

  20. Ganem D, Varmus HE. The molecular biology of the hepatitis B viruses. Ann Rev Biochem 56:651–693;1987.

    Google Scholar 

  21. Gao WY, Cara A, Gallo RC, Lori F. Low levels of deoxynucleotides in peripheral blood lymphocytes: A strategy to inhibit human immunodeficiency virus type 1 replication. Proc Natl Acad Sci USA 90:8925–8928;1993.

    Google Scholar 

  22. Gordon C, McGurk G, Dillon P, Rosen C, Hastie ND. Defective mitosis due to a mutation in the gene for a fission yeast 26S protease subunit. Nature 366:355–357;1993.

    Google Scholar 

  23. Goulaoui H, Subra F, Mouscaded JF, Carteau S, Auclair C. Exogenous nucleosides promote the completion of MoMLV DNA synthesis in G0-arrested Balb c/3T3 fibroblasts. Virology 200:87–97;1994.

    Google Scholar 

  24. Guo WT, Bell KD, Ou JH. Characterization of the hepatitis B virus EnhI enhancer and X promoter complex. J Virol 65:6686–6692;1991.

    Google Scholar 

  25. Guo WT, Wang J, Tam G, Yen TS, Ou JS. Leaky transcription termination produces larger and smaller than genome size hepatitis B virus X gene transcripts. Virology 181:630–636;1991.

    Google Scholar 

  26. Haruna Y, Hayashi N, Katayama K, Yuki N, Kasahara A, Sasaki Y, Fusamoto H, Kamada T. Expression of X protein and hepatitis B virus replication in chronic hepatitis. Hepatology 13:417–421;1991.

    Google Scholar 

  27. Hess J, Stemler M, Will H, Schroder CH, Kuhn J, Braun R. Frequent detection of antibodies to hepatitis B virus x-protein in acute, chronic and resolved infections. Med Microbiol Immunol (Berl) 177:195–205;1988.

    Google Scholar 

  28. Hohne M, Schaefer S, Seifer M, Feitelson MA, Paul D, Gerlich WH. Malignant transformation of immortalized transgenic hepatocytes after transfection with hepatitis B virus DNA. EMBO J 9:1137–1145;1990.

    Google Scholar 

  29. Hollinger FB. Hepatitis B virus. In: Fields BN, Knipe DM eds. Virology. New York, Raven Press, 2171–2238;1990.

    Google Scholar 

  30. Hsu IC, Metcalf RA, Sun T, Welsh JA, Wang NJ, Harris CC. Mutational hotspot in the p53 gene in human hepatocellular carcinomas. Nature 350:427–428;1991.

    Google Scholar 

  31. Ichimura H, Levy JA. Polymerase substrate depletion: A novel strategy for inhibiting the replication of the human immunodeficiency virus. Virology 211:554–560;1995.

    Google Scholar 

  32. Kanno T, Brown K, Siebenlist U. Evidence in support of a role for human T-cell leukemia virus type I Tax in activating NF-kappa B via stimulation of signaling pathways. J Biol Chem 270:11745–11748;1995.

    Google Scholar 

  33. Kay A, Dupont de Dinechin S, Vitvitski TL, Mandart E, Shamoon BM, Galibert F. Recognition of the N-terminal, C-terminal, and interior portions of HBx by sera from patients with hepatitis B. J Med Virol 33:228–235;1991.

    Google Scholar 

  34. Kekule AS, Lauer U, Weiss L, Luber B, Hofschneider PH. Hepatitis B virus transactivator HBx uses a tumour promoter signalling pathway. Nature 361:742–745;1993.

    Google Scholar 

  35. Kido H, Fukutomi A, Katunuma N. A novel membrane-bound serine esterase in human T4+ lymphocytes immunologically reactive with antibody inhibiting syncytia induced by HIV-1: Purification and characterization. J Biol Chem 265:21979–21985;1990.

    Google Scholar 

  36. Kim CM, Koike K, Saito I, Miyamura T, Jay G. HBx gene of hepatitis B virus induces liver cancer in transgenic mice. Nature 351:317–320;1991.

    Google Scholar 

  37. Kim YH, Kang SK, Lee YI. Functional analysis of hepatitis B virus transactivator X: Implication of the leucine zipper-like region and C-terminal seven conserved amino acids in functional regions. Biochem Biophys Res Commun 197:894–903;1993.

    Google Scholar 

  38. Koike K, Moriya K, Yotsuyanagi H, Iino S, Kurokawa K. Induction of cell cycle progression by hepatitis B virus HBx gene expression in quiescent mouse fibroblasts. J Clin Invest 94:44–49;1994.

    Google Scholar 

  39. Kwee L, Lucito R, Aufiero B, Schneider RJ. Alternate translation initiation on hepatitis B virus X mRNA produces multiple polypeptides that differentially transactivate class II and III promoters. J Virol 66:4382–4389;1992.

    Google Scholar 

  40. Lee TH, Finegold MJ, Shen RF, DeMayo JL, Woo SL, Butel JS. Hepatitis B virus transactivator X protein is not tumorigenic in transgenic mice. J Virol 64:5939–5947;1990.

    Google Scholar 

  41. Lee TH, Elledge SJ, Butel JS. Hepatitis B virus X protein interacts with a probable cellular DNA repair protein. J Virol 69:1107–1114;1995.

    Google Scholar 

  42. Levrero M, Jean JO, Balsano C, Will H, Perricaudet M. Hepatitis B virus (HBV) X gene expression in human cells and anti-HBx antibodies detection in chronic HBV infection. Virology 174:299–304;1990.

    Google Scholar 

  43. Levrero M, Stemler M, Pasquinelli C, Alberti A, Jean JO, Franco A, Balsano C, Diop D, Brechot C, Melegari M, et al. Significance of anti-HBx antibodies in hepatitis B virus infection. Hepatology 13:143–149;1991.

    Google Scholar 

  44. Liu F, Green MR. Promoter targeting by adenovirus Ela through interaction with different cellular DNA-binding domains. Nature 368:520–525;1994.

    Google Scholar 

  45. Lucito R, Schneider RJ. Hepatitis B virus X protein activates transcription factor NF-kappa B without a requirement for protein kinase C. J Virol 66:983–991;1992.

    Google Scholar 

  46. Maguire HF, Hoeffler JP, Siddiqui A. HBV X protein alters the DNA binding specificity of CREB and ATF-2 by protein-protein interactions. Science 252:842–844;1991.

    Google Scholar 

  47. Mahe Y, Mukaida N, Kuno K, Akiyama M, Ikeda N, Matsushima K, Murakami S. Hepatitis B virus X protein transactivates human interleukin-8 gene through acting on nuclear factor kB and CCAAT/enhancer-binding protein-like cis-elements. J Biol Chem 266:13759–13763;1991.

    Google Scholar 

  48. Miller RH, Robinson WS. Common evolutionary origin of hepatitis B virus and retroviruses. Proc Natl Acad Sci USA 83:2531–2535;1986.

    Google Scholar 

  49. Murakami S, Cheong JH, Kaneko S. Human hepatitis virus X gene encodes a regulatory domain that represses transactivation of X protein. J Biol Chem 269:15118–15123;1994.

    Google Scholar 

  50. Murakami S, Cheong J, Ohno S, Matsushima K, Kaneko S. Transactivation of human hepatitis B virus X protein, HBx, operates through a mechanism distinct from protein kinase C and okadaic acid activation pathways. Virology 199:243–246;1994.

    Google Scholar 

  51. Nagashima H, Imai M, Iwakura Y. Aberrant tissue specific expression of the transgene in transgenic mice that carry the hepatitis B virus genome defective in the X gene. Arch Virol 132:381–397;1993.

    Google Scholar 

  52. Nakamura I, Koike K. Identification of a binding protein to the X gene promoter region of hepatitis B virus. Virology 191:533–540;1992.

    Google Scholar 

  53. Nakatake H, Chisaka O, Yamamoto S, Matsubara K, Koshy R. Effect of X protein on transactivation of hepatitis B virus promoters and on viral replication. Virology 195:305–314;1993.

    Google Scholar 

  54. Natoli G, Avantaggiati ML, Chirillo P, Puri PL, Ianni A, Balsano C, Levrero M. Ras- and Raf-dependent activation of c-jun transcriptional activity by the hepatitis B virus transactivator pX. Oncogene 9:2837–2843;1994.

    Google Scholar 

  55. Natoli G, Avantaggiati ML, Chirillo P, Costanzo A, Artini M, Balsano C, Levrero M. Induction of the DNA-binding activity of c-jun/c-fos heterodimers by the hepatitis B virus transactivator pX. Mol Cell Biol 14:989–998;1994.

    Google Scholar 

  56. Papa FR, Hochstrasser M. The yeast DOA4 gene encodes a deubiquitinating enzyme related to a product of the human tre-2 oncogene. Nature 366:313–319;1993.

    Google Scholar 

  57. Pfaff E, Salfeld J, Gmelin K, Schaller H, Theilmann L. Synthesis of the X-protein of hepatitis B virus in vitro and detection of anti-X antibodies in human sera. Virology 158:456–460;1987.

    Google Scholar 

  58. Puisieux A, Ji J, Guillot C, Legros Y, Soussi T, Isselbacher K, Ozturk M. p53-mediated cellular response to DNA damage in cells with replicative hepatitis B virus. Proc Natl Acad Sci USA 92:1342–1346;1995.

    Google Scholar 

  59. Qadri I, Maguire HF, Siddiqui A. Hepatitis B virus transactivator protein X interacts with the TATA-binding protein. Proc Natl Acad Sci USA 92:1003–1007;1995.

    Google Scholar 

  60. Renner M, Haniel A, Buergelt E, Hofschneider PH, Koch W. Transactivating function and expression of the x gene of hepatitis B virus. J Hepatol 23:53–65;1995.

    Google Scholar 

  61. Rossner MT. Review: Hepatitis B virus X-gene product: A promiscuous transcriptional activator. J Med Virol 36:101–117;1992.

    Google Scholar 

  62. Rothnie HM, Chapdelaine Y, Hohn T. Pararetroviruses and retroviruses: a comparative review of viral structure and gene expression strategies. Adv Virus Res 44:1–67;1994.

    Google Scholar 

  63. Runkel L, Fischer M, Schaller H. Two-codon insertion mutations of the HBx define two separate regions necessary for its trans-activation function. Virology 197:529–536;1993.

    Google Scholar 

  64. Schek N, Bartenschlager R, Kuhn C, Schaller H. Phosphorylation and rapid turnover of hepatitis B virus X-protein expressed in HepG2 cells from a recombinant vaccinia virus. Oncogene 6:1735–1744;1991.

    Google Scholar 

  65. Scorsone KA, Zhou YZ, Butel JS, Slagle BL. p53 mutations cluster at codon 249 in hepatitis B virus-positive hepatocellular carcinomas from China. Cancer Res 52:1635–1638;1992.

    Google Scholar 

  66. Semmes OJ, Jeang KT. Definition of a minimal activation domain in human T-cell leukemia virus type I Tax. J Virol 69:1827–1833;1995.

    Google Scholar 

  67. Seroz T, Hwang JR, Moncollin V, Egly JM. TFIIH: A link between transcription, DNA repair and cell cycle regulation. Curr Opin Genet Dev 5:217–221;1995.

    Google Scholar 

  68. Seto E, Yen TS, Peterlin BM, Ou JH. Transactivation of the human immunodeficiency virus long terminal repeat by the hepatitis B virus X protein. Proc Natl Acad Sci USA 85:8286–8290;1988.

    Google Scholar 

  69. Seto E, Zhou DX, Peterlin BM, Yen TS. Transactivation by the hepatitis B virus X protein shows cell-type specificity. Virology 173:764–766;1989.

    Google Scholar 

  70. Seto E, Mitchell PJ, Yen TS. Transactivation by the hepatitis B virus X protein depends on AP-2 and other transcription factors. Nature 344:72–74;1990.

    Google Scholar 

  71. Seto E, Yen TS. Mutual functional antagonism of the simian virus 40 T antigen and the hepatitis B virus trans activator. J Virol 65:2351–2356;1991.

    Google Scholar 

  72. Shibuya H, Irie K, Ninomiya TJ, Goebl M, Taniguchi, Matsumoto K. New human gene encoding a positive modulator of HIV Tat-mediated transactivation. Nature 357:700–702;1992.

    Google Scholar 

  73. Siddiqui A, Jameel S, Mapoles J. Expression of the hepatitis B virus X gene in mammalian cells. Proc Natl Acad Sci USA 84:2513–2517;1987.

    Google Scholar 

  74. Spandau DF, Lee CH. Trans-activation of viral enhancers by the hepatitis B virus X protein. J Virol 62:427–434;1988.

    Google Scholar 

  75. Sugata F, Chen HS, Kaneko S, Purcell RH, Miller RH. Analysis of the X gene promoter of woodchuck hepatitis virus. Virology 205:314–320;1994.

    Google Scholar 

  76. Takada S, Kido H, Fukutomi A, Mori T, Koike K. Interaction of hepatitis B virus X protein with a serine protease, tryptase TL2 as an inhibitor. Oncogene 9:341–348;1994.

    Google Scholar 

  77. Treinin M, Laub O. Identification of a promoter element located upstream from the hepatitis B virus X gene. Mol Cell Biol 7:545–548;1987.

    Google Scholar 

  78. Truant R, Antunovic J, Greenblatt J, Prives C, Cromlish JA. Direct interaction of the hepatitis B virus HBx protein with p53 leads to inhibition by HBx of p53 response element-directed transactivation. J Virol 69:1851–1859;1995.

    Google Scholar 

  79. Twu JS, Rosen CA, Haseltine WA, Robinson WS. Identification of a region within the human immunodeficiency virus type 1 long terminal repeat that is essential for transactivation by the hepatitis B virus gene X. J Virol 63:2857–2860;1989.

    Google Scholar 

  80. Unger T, Shaul Y. The X protein of the hepatitis B virus acts as a transcription factor when targeted to its responsive element. EMBO J 9:1889–1895;1990.

    Google Scholar 

  81. Wagner S, Green MR. HTLV-I Tax protein stimulation of DNA binding of bZIP proteins by enhancing dimerization. Science 262:395–399;1993.

    Google Scholar 

  82. Wang XW, Forrester K, Yeh H, Feitelson MA, Gu JR, Harris CC. Hepatitis B virus X protein inhibits p53 sequence-specific DNA binding, transcriptional activity, and association with transcription factor ERCC3. Proc Natl Acad Sci USA 91:2230–2234;1994.

    Google Scholar 

  83. Wild CP, Jansen LA, Cova L, Montesano R. Molecular dosimetry of aflatoxin exposure: Contribution to understanding the multifactorial etiopathogenesis of primary hepatocellular carcinoma with particular reference to hepatitis B virus. Environ Health Perspect 99:115–122;1993.

    Google Scholar 

  84. Williams JS, Andrisani OM. The hepatitis B virus X protein targets the basic region-leucine zipper domain of CREB. Proc Natl Acad Sci USA 92:3819–3823;1995.

    Google Scholar 

  85. Wu JY, Zhou ZY, Judd A, Cartwright CA, Robinson WS. The hepatitis B virus-encoded transcriptional trans-activator hbx appears to be a novel protein serine/threonine kinase [published erratum appears in Cell 75:826;1993]. Cell 63:687–695;1990.

    Google Scholar 

  86. Yen TSB. Regulation of hepatitis B virus gene expression. Seminars Virol 4:33–42;1993.

    Google Scholar 

  87. Zentgraf H, Herrmann G, Klein R, Schranz P, Loncarevic I, Herrmann D, Hubner K, Schroder CH. Mouse monoclonal antibody directed against hepatitis B virus X protein synthesized inEscherichia coli: Detection of reactive antigen in liver cell carcinoma and chronic hepatitis. Oncology 47:143–148;1990.

    Google Scholar 

  88. Zheng YW, Riegler J, Wu J, Yen TS. Novel short transcripts of hepatitis B virus X gene derived from intragenic promoter. J Biol Chem 269:22593–22598;1994.

    Google Scholar 

  89. Zhou DX, Taraboulos A, Ou JH, Yen TS. Activation of class I major histocompatibility complex gene expression by hepatitis B virus. J Virol 64:4025–4028;1990.

    Google Scholar 

  90. Zoulim F, Saputelli J, Seeger C. Woodchuck hepatitis virus X protein is required for viral infection in vivo. J Virol 68:2026–2030;1994.

    Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Pathology Service 113B, Veterans Affairs Medical Center, and Department of Pathology, University of California, San Francisco, Calif., USA

    T. S. Benedict Yen

Authors
  1. T. S. Benedict Yen
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

Benedict Yen, T.S. Hepadnaviral X protein: Review of recent progress. J Biomed Sci 3, 20–30 (1996). https://doi.org/10.1007/BF02253575

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1007/BF02253575

Key Words

Search

Navigation