1887

Abstract

Polyomavirus JC (JCV) infects oligodendrocytes and astrocytes in the brain and is the cause of the demyelinating disease progressive multifocal leukoencephalopathy (PML). In cell culture, JCV infection is characterized by severe damage to cellular DNA, which begins early in infection, and a viral cytopathic effect, which is observed late in infection. Nevertheless, these JCV-infected cells show a low level of apoptosis, at both the early and late stages of infection. This suggests that there is conflicting interplay between viral anti-apoptotic pathways that seek to optimize virus production, e.g. through T antigen (T-Ag)–p53 interaction, and cellular pro-apoptotic pathways that seek to eliminate virally infected cells. The apoptosis regulatory protein BAG3 is a member of the human Bcl-2-associated athanogene (BAG) family of proteins, which function as molecular co-chaperones through their interaction with Hsc70/Hsp70 and function in the regulation of the cellular stress response, proliferation and apoptosis. This study showed that BAG3 protein is downregulated upon JCV infection and that this effect is mediated by JCV T-Ag via repression of the BAG3 promoter. The site of action of T-Ag was mapped to an AP2 site in the BAG3 promoter, and gel shift and chromatin immunoprecipitation assays showed that T-Ag inhibited AP2 binding to this site, resulting in downregulation of BAG3 promoter expression. Using BAG3 and T-Ag expression and BAG3 siRNA, it was found that BAG3 and T-Ag had antagonistic effects on the induction of apoptosis, being anti-apoptotic and pro-apoptotic, respectively. The significance of these interactions to the JCV life cycle is discussed.

Loading

Article metrics loading...

/content/journal/jgv/10.1099/vir.0.008722-0
2009-07-01
2024-03-28
Loading full text...

Full text loading...

/deliver/fulltext/jgv/90/7/1629.html?itemId=/content/journal/jgv/10.1099/vir.0.008722-0&mimeType=html&fmt=ahah

References

  1. Amini S., Mameli G., Del Valle L., Skowronska A., Reiss K., Gelman B. B., White M. K., Khalili K., Sawaya B. E. 2005; p73 interacts with human immunodeficiency virus type 1 Tat in astrocytic cells and prevents its acetylation on lysine 28. Mol Cell Biol 25:8126–8138 [CrossRef]
    [Google Scholar]
  2. Bonelli P., Petrella A., Rosati A., Romano M. F., Lerose R., Pagliuca M. G., Amelio T., Festa M., Martire G. other authors 2004; BAG3 protein regulates stress-induced apoptosis in normal and neoplastic leukocytes. Leukemia 18:358–360 [CrossRef]
    [Google Scholar]
  3. Brive L., Takayama S., Briknarová K., Homma S., Ishida S. K., Reed J. C., Ely K. R. 2001; The carboxyl-terminal lobe of Hsc70 ATPase domain is sufficient for binding to BAG1. Biochem Biophys Res Commun 289:1099–1105 [CrossRef]
    [Google Scholar]
  4. Cole C. N. 1996; Polyomavirinae : the viruses and their replication. In Fundamental Virology , 3rd edn. pp 917–946Edited by Fields B. N., Knipe D. M., Howley P. M. Philadelphia: Lippincott, Williams & Wilkins;
    [Google Scholar]
  5. Darbinian-Sarkissian N., Czernik M., Peruzzi F., Gordon J., Rappaport J., Reiss K., Khalili K., Amini S. 2006; Dysregulation of NGF-signaling and Egr-1 expression by Tat in neuronal cell culture. J Cell Physiol 208:506–515 [CrossRef]
    [Google Scholar]
  6. Darbinyan A., White M. K., Akan S., Radhakrishnan S., Del Valle L., Amini S., Khalili K. 2007; Alterations of DNA damage repair pathways resulting from JCV infection. Virology 364:73–86 [CrossRef]
    [Google Scholar]
  7. DeCaprio J. A. 1999; The role of the J domain of SV40 large T in cellular transformation. Biologicals 27:23–28 [CrossRef]
    [Google Scholar]
  8. Del Valle L., Gordon J., Enam S., Delbue S., Croul S., Abraham S., Radhakrishnan S., Assimakopoulou M., Katsetos C. D., Khalili K. 2002; Expression of human neurotropic polyomavirus JCV late gene product agnoprotein in human medulloblastoma. J Natl Cancer Inst 94:267–273 [CrossRef]
    [Google Scholar]
  9. Del Valle L., White M. K., Khalili K. 2008; Potential mechanisms of the human polyomavirus JC in neural oncogenesis. J Neuropathol Exp Neurol 67:729–740 [CrossRef]
    [Google Scholar]
  10. Devireddy L. R., Kumar K. U., Pater M. M., Pater A. 2000; BAG-1, a novel Bcl-2-interacting protein, activates expression of human JC virus. J Gen Virol 81:351–357
    [Google Scholar]
  11. Doong H., Price J., Kim Y. S., Gasbarre C., Probst J., Liotta L. A., Blanchette J., Rizzo K., Kohn E. 2000; CAIR-1/BAG-3 forms an EGF-regulated ternary complex with phospholipase C- γ and Hsp70/Hsc70. Oncogene 19:4385–4395 [CrossRef]
    [Google Scholar]
  12. Doong H., Vrailas A., Kohn E. C. 2002; What's in the ‘BAG’? – a functional domain analysis of the BAG-family proteins. Cancer Lett 188:25–32 [CrossRef]
    [Google Scholar]
  13. Doong H., Rizzo K., Fang S., Kulpa V., Weissman A. M., Kohn E. C. 2003; CAIR-1/BAG-3 abrogates heat shock protein-70 chaperone complex-mediated protein degradation: accumulation of poly-ubiquitinated Hsp90 client proteins. J Biol Chem 278:28490–28500 [CrossRef]
    [Google Scholar]
  14. Franceschelli S., Rosati A., Lerose R., De Nicola S., Turco M. C., Pascale M. 2008; BAG3 gene expression is regulated by heat shock factor 1. J Cell Physiol 215:575–577 [CrossRef]
    [Google Scholar]
  15. Frisque R. J., White F. A. 1992; The molecular biology of JC virus, causative agent of progressive multifocal leukoencephalopathy. In Molecular Neurovirology pp 25–160Edited by Roos R. P. Totawa, NJ: Humana Press;
    [Google Scholar]
  16. Frisque R. J., Bream G. L., Cannella M. T. 1984; Human polyomavirus JC virus genome. J Virol 51:458–469
    [Google Scholar]
  17. Gentilella A., Passiatore G., Deshmane S., Turco M. C., Khalili K. 2008; Activation of BAG3 by Egr-1 in response to FGF-2 in neuroblastoma cells. Oncogene 27:5011–5018 [CrossRef]
    [Google Scholar]
  18. Graham F. L., van der Eb A. J. 1973; A new technique for the assay of infectivity of human adenovirus 5 DNA. Virology 52:456–467 [CrossRef]
    [Google Scholar]
  19. Hou J., Major E. O. 2000; Progressive multifocal leukoencephalopathy: JC virus induced demyelination in the immune compromised host. J Neurovirol 6:Suppl. 2S98–S100
    [Google Scholar]
  20. Kabbage M., Dickman M. B. 2008; The BAG proteins: a ubiquitous family of chaperone regulators. Cell Mol Life Sci 65:1390–1402 [CrossRef]
    [Google Scholar]
  21. Kassis J. N., Guancial E. A., Doong H., Virador V., Kohn E. C. 2006; CAIR-1/BAG-3 modulates cell adhesion and migration by downregulating activity of focal adhesion proteins. Exp Cell Res 312:2962–2971 [CrossRef]
    [Google Scholar]
  22. Kelley W. L., Georgopoulos C. 1997; The T/t common exon of simian virus 40, JC, and BK polyomavirus T antigens can functionally replace the J-domain of the Escherichia coli DnaJ molecular chaperone. Proc Natl Acad Sci U S A 94:3679–3684 [CrossRef]
    [Google Scholar]
  23. Khalili K., Gordon J., White M. K. 2006; The polyomavirus, JCV and its involvement in human disease. Adv Exp Med Biol 577:274–287
    [Google Scholar]
  24. Krynska B., Gordon J., Otte J., Franks R., Knobler R., DeLuca A., Giordano A., Khalili K. 1997; Role of cell cycle regulators in tumor formation in transgenic mice expressing the human neurotropic virus, JCV, early protein. J Cell Biochem 67:223–230 [CrossRef]
    [Google Scholar]
  25. Lane D. P., Crawford L. V. 1979; T antigen is bound to a host protein in SV40-transformed cells. Nature 278:261–263 [CrossRef]
    [Google Scholar]
  26. Lassak A., Del Valle L., Peruzzi F., Wang J. Y., Enam S., Croul S., Khalili K., Reiss K. 2002; Insulin receptor substrate 1 translocation to the nucleus by the human JC virus T-antigen. J Biol Chem 277:17231–17238 [CrossRef]
    [Google Scholar]
  27. Lee J. H., Takahashi T., Yasuhara N., Inazawa J., Kamada S., Tsujimoto Y. 1999; Bis, a Bcl-2-binding protein that synergizes with Bcl-2 in preventing cell death. Oncogene 18:6183–6190 [CrossRef]
    [Google Scholar]
  28. Linzer D. I., Levine A. J. 1979; Characterization of a 54K Dalton cellular SV40 tumor antigen present in SV40-transformed cells and uninfected embryonal carcinoma cells. Cell 17:43–52 [CrossRef]
    [Google Scholar]
  29. Mázló M., Ressetar H. G., Stoner G. L. 2001; The neuropathology and pathogenesis of progressive multifocal leukoencephalopathy. In Human Polyomaviruses: Molecular and Clinical Perspectives pp 257–335Edited by Khalili K., Stoner G. L. New York: Wiley;
    [Google Scholar]
  30. McPherson L. A., Weigel R. J. 1999; AP2 α and AP2 γ : a comparison of binding site specificity and trans-activation of the estrogen receptor promoter and single site promoter constructs. Nucleic Acids Res 27:4040–4049 [CrossRef]
    [Google Scholar]
  31. Mitchell P. J., Wang C., Tjian R. 1987; Positive and negative regulation of transcription in vitro : enhancer-binding protein AP-2 is inhibited by SV40 T antigen. Cell 50:847–861 [CrossRef]
    [Google Scholar]
  32. Pagliuca M. G., Lerose R., Cigliano S., Leone A. 2003; Regulation by heavy metals and temperature of the human BAG-3 gene, a modulator of Hsp70 activity. FEBS Lett 541:11–15 [CrossRef]
    [Google Scholar]
  33. Piña-Oviedo S., Urbanska K., Radhakrishnan S., Sweet T., Reiss K., Khalili K., Del Valle L. 2007; Effects of JC virus infection on anti-apoptotic protein survivin in progressive multifocal leukoencephalopathy. Am J Pathol 170:1291–1304 [CrossRef]
    [Google Scholar]
  34. Radhakrishnan S., Otte J., Enam S., Del Valle L., Khalili K., Gordon J. 2003; JC virus-induced changes in cellular gene expression in primary human astrocytes. J Virol 77:10638–10644 [CrossRef]
    [Google Scholar]
  35. Radhakrishnan S., Gordon J., Del Valle L., Cui J., Khalili K. 2004; Intracellular approach for blocking JC virus gene expression by using RNA interference during viral infection. J Virol 78:7264–7269 [CrossRef]
    [Google Scholar]
  36. Romagnoli L., Sariyer I. K., Tung J., Feliciano M., Sawaya B. E., Del Valle L., Ferrante P., Khalili K., Safak M., White M. K. 2008; Early growth response-1 protein is induced by JC virus infection and binds and regulates the JC virus promoter. Virology 375:331–341 [CrossRef]
    [Google Scholar]
  37. Rosati A., Ammirante M., Gentilella A., Basile A., Festa M., Pascale M., Marzullo L., Belisario M. A., Tosco A. & other authors (2007a). Apoptosis inhibition in cancer cells: a novel molecular pathway that involves BAG3 protein. Int J Biochem Cell Biol 39:1337–1342 [CrossRef]
    [Google Scholar]
  38. Rosati A., Leone A., Del Valle L., Amini S., Khalili K., Turco M. C. 2007b; Evidence for BAG3 modulation of HIV-1 gene transcription. J Cell Physiol 210:676–683 [CrossRef]
    [Google Scholar]
  39. Rosati A., Khalili K., Deshmane S. L., Radhakrishnan S., Pascale M., Turco M. C., Marzullo L. 2009; BAG3 protein regulates caspase-3 activation in HIV-1-infected human primary microglial cells. J Cell Physiol 218:264–267 [CrossRef]
    [Google Scholar]
  40. Sawai E. T., Butel J. S. 1989; Association of a cellular heat shock protein with simian virus 40 large T antigen in transformed cells. J Virol 63:3961–3973
    [Google Scholar]
  41. Seth P., Diaz F., Tao-Cheng J. H., Major E. O. 2004; JC virus induces nonapoptotic cell death of human central nervous system progenitor cell-derived astrocytes. J Virol 78:4884–4891 [CrossRef]
    [Google Scholar]
  42. Somasundaram K., Jayaraman G., Williams T., Moran E., Frisch S., Thimmapaya B. 1996; Repression of a matrix metalloprotease gene by E1A correlates with its ability to bind to cell type-specific transcription factor AP-2. Proc Natl Acad Sci U S A 93:3088–3093 [CrossRef]
    [Google Scholar]
  43. Takayama S., Sato T., Krajewski S., Kochel K., Irie S., Millan J. A., Reed J. C. 1995; Cloning and functional analysis of BAG-1: a novel Bcl-2-binding protein with anti-cell death activity. Cell 80:279–284 [CrossRef]
    [Google Scholar]
  44. Takayama S., Xie Z., Reed J. C. 1999; An evolutionarily conserved family of Hsp70/Hsc70 molecular chaperone regulators. J Biol Chem 274:781–786 [CrossRef]
    [Google Scholar]
  45. Verma S., Ziegler K., Ananthula P., Co J. K., Frisque R. J., Yanagihara R., Nerurkar V. R. 2006; JC virus induces altered patterns of cellular gene expression: interferon-inducible genes as major transcriptional targets. Virology 345:457–467 [CrossRef]
    [Google Scholar]
  46. White M. K., Khalili K. 2004; Polyomaviruses and human cancer: molecular mechanisms underlying patterns of tumorigenesis. Virology 324:1–16 [CrossRef]
    [Google Scholar]
  47. White M. K., McCubrey J. A. 2001; Suppression of apoptosis: role in cell growth and neoplasia. Leukemia 15:1011–1021 [CrossRef]
    [Google Scholar]
  48. White M. K., Amini S., Khalili K., Darbinian N. 2008; Development of a bidirectional caspase-3 expression system for the induction of apoptosis. Cancer Biol Ther 7:945–954 [CrossRef]
    [Google Scholar]
http://instance.metastore.ingenta.com/content/journal/jgv/10.1099/vir.0.008722-0
Loading
/content/journal/jgv/10.1099/vir.0.008722-0
Loading

Data & Media loading...

This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error