1887

Abstract

Kaposi's sarcoma (KS)-associated herpesvirus (KSHV) proteins ORF57 (also known as MTA) and ORF50 (also known as RTA) act post-transcriptionally and transcriptionally to regulate viral lytic gene expression and synergistically activate certain early and late KSHV promoters. When ORF57 and ORF50 were co-expressed, they co-operatively stimulated expression from the promoter of the immediate-early ORF50 gene itself. Co-immunoprecipitations with extracts of KSHV-infected cells showed that ORF57 and ORF50 proteins were present in the same complex. Using the pull-down assay with extracts of KSHV-infected cells, ORF50 protein was shown to interact with a glutathione -transferase–ORF57 fusion protein. A chromatin immunoprecipitation assay showed that ORF50 promoter sequences were preferentially associated with immunoprecipitated chromatin using both anti-ORF50 and anti-ORF57 antibodies consistent with both an physical association between ORF57 and ORF50 and a potential role for ORF57 at the transcriptional level. This is the first demonstration of an interaction between these two lytic regulatory proteins in a gammaherpesvirus. Expression of ORF50 protein is sufficient to induce lytic replication in latently infected cells and may determine viral host range, spread and KS pathogenesis . A new insight into the co-ordinated activities of these two key regulatory proteins is provided in which upregulation of the ORF50 promoter with augmentation of ORF50 activity by ORF57 protein, and vice versa, would facilitate the cascade of lytic viral gene expression, thereby breaking latency. A functional and physical interaction between these two gammaherpesvirus regulatory protein counterparts could be a general feature of the herpesviruses.

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2004-08-01
2019-11-19
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References

  1. Bechtel, J. T., Liang, Y., Hvidding, J. & Ganem, D. ( 2003; ). Host range of Kaposi's sarcoma-associated herpesvirus in cultured cells. J Virol 77, 6474–6481.[CrossRef]
    [Google Scholar]
  2. Bello, L. J., Davison, A. J., Glenn, M. A., Whitehouse, A., Rethmeier, N., Schulz, T. F. & Clements, J. B. ( 1999; ). The human herpesvirus-8 ORF 57 gene and its properties. J Gen Virol 80, 3207–3215.
    [Google Scholar]
  3. Boshoff, C. & Chang, Y. ( 2001; ). Kaposi's sarcoma-associated herpesvirus: a new DNA tumor virus. Annu Rev Med 52, 453–470.[CrossRef]
    [Google Scholar]
  4. Boshoff, C. & Weiss, R. A. ( 2001; ). Epidemiology and pathogenesis of Kaposi's sarcoma-associated herpesvirus. Philos Trans R Soc Lond B Biol Sci 356, 517–534.[CrossRef]
    [Google Scholar]
  5. Boshoff, C., Schulz, T. F., Kennedy, M. M., Graham, A. K., Fisher, C., Thomas, A., McGee, J. O., Weiss, R. A. & O'Leary, J. J. ( 1995; ). Kaposi's sarcoma-associated herpesvirus infects endothelial and spindle cells. Nat Med 1, 1274–1278.[CrossRef]
    [Google Scholar]
  6. Chang, Y., Cesarman, E., Pessin, M. S., Lee, F., Culpepper, J., Knowles, D. M. & Moore, P. S. ( 1994; ). Identification of herpesvirus-like DNA sequences in AIDS-associated Kaposi's sarcoma. Science 266, 1865–1869.[CrossRef]
    [Google Scholar]
  7. Chang, P. J., Shedd, D., Gradoville, L., Cho, M. S., Chen, L. W., Chang, J. & Miller, G. ( 2002; ). Open reading frame 50 protein of Kaposi's sarcoma-associated herpesvirus directly activates the viral PAN and K12 genes by binding to related response elements. J Virol 76, 3168–3178.[CrossRef]
    [Google Scholar]
  8. Cunningham, C., Barnard, S., Blackbourn, D. J. & Davison, A. J. ( 2003; ). Transcription mapping of human herpesvirus 8 genes encoding viral interferon regulatory factors. J Gen Virol 84, 1471–1483.[CrossRef]
    [Google Scholar]
  9. Deng, H., Young, A. & Sun, R. ( 2000; ). Auto-activation of the RTA gene of human herpesvirus-8/Kaposi's sarcoma-associated herpesvirus. J Gen Virol 81, 3043–3048.
    [Google Scholar]
  10. Dourmishev, L. A., Dourmishev, A. L., Palmeri, D., Schwartz, R. A. & Lukac, D. M. ( 2003; ). Molecular genetics of Kaposi's sarcoma-associated herpesvirus (human herpesvirus 8) epidemiology and pathogenesis. Microbiol Mol Biol Rev 67, 175–212.[CrossRef]
    [Google Scholar]
  11. Foreman, K. E., Friborg, J., Jr, Kong, W. P., Woffendin, C., Polverini, P. J., Nickoloff, B. J. & Nabel, G. J. ( 1997; ). Propagation of a human herpesvirus from AIDS-associated Kaposi's sarcoma. N Engl J Med 336, 163–171.[CrossRef]
    [Google Scholar]
  12. Goodwin, D. J., Hall, K. T., Giles, M. S., Calderwood, M. A., Markham, A. F. & Whitehouse, A. ( 2000; ). The carboxy terminus of the herpesvirus saimiri ORF 57 gene contains domains that are required for transactivation and transrepression. J Gen Virol 81, 2253–2265.
    [Google Scholar]
  13. Gradoville, L., Gerlach, J., Grogan, E., Shedd, D., Nikiforow, S., Metroka, C. & Miller, G. ( 2000; ). Kaposi's sarcoma-associated herpesvirus open reading frame 50/RTA protein activates the entire viral lytic cycle in the HH-B2 primary effusion lymphoma cell line. J Virol 74, 6207–6212.[CrossRef]
    [Google Scholar]
  14. Gupta, A. K., Ruvolo, V., Patterson, C. & Swaminathan, S. ( 2000; ). The human herpesvirus 8 homolog of Epstein–Barr virus SM protein (KS-SM) is a posttranscriptional activator of gene expression. J Virol 74, 1038–1044.[CrossRef]
    [Google Scholar]
  15. Hardwick, J. M., Lieberman, P. M. & Hayward, S. D. ( 1988; ). A new Epstein–Barr virus transactivator, R, induces expression of a cytoplasmic early antigen. J Virol 62, 2274–2284.
    [Google Scholar]
  16. Jean, S., LeVan, K. M., Song, B., Levine, M. & Knipe, D. M. ( 2001; ). Herpes simplex virus 1 ICP27 is required for transcription of two viral late (gamma 2) genes in infected cells. Virology 283, 273–284.[CrossRef]
    [Google Scholar]
  17. Kenney, S., Kamine, J., Holley-Guthrie, E., Mar, E. C., Lin, J. C., Markovitz, D. & Pagano, J. ( 1989; ). The Epstein–Barr virus immediate-early gene product, BMLF1, acts in trans by a posttranscriptional mechanism which is reporter gene dependent. J Virol 63, 3870–3877.
    [Google Scholar]
  18. Kirshner, J. R., Lukac, D. M., Chang, J. & Ganem, D. ( 2000; ). Kaposi's sarcoma-associated herpesvirus open reading frame 57 encodes a posttranscriptional regulator with multiple distinct activities. J Virol 74, 3586–3597.[CrossRef]
    [Google Scholar]
  19. Koffa, M. D., Clements, J. B., Izaurralde, E., Wadd, S., Wilson, S. A., Mattaj, I. W. & Kuersten, S. ( 2001; ). Herpes simplex virus ICP27 protein provides viral mRNAs with access to the cellular mRNA export pathway. EMBO J 20, 5769–5778.[CrossRef]
    [Google Scholar]
  20. Liang, Y. & Ganem, D. ( 2003; ). Lytic but not latent infection by Kaposi's sarcoma-associated herpesvirus requires host CSL protein, the mediator of Notch signaling. Proc Natl Acad Sci U S A 100, 8490–8495.[CrossRef]
    [Google Scholar]
  21. Liang, Y., Chang, J., Lynch, S. J., Lukac, D. M. & Ganem, D. ( 2002; ). The lytic switch protein of KSHV activates gene expression via functional interaction with RBP-Jκ (CSL), the target of the Notch signaling pathway. Genes Dev 16, 1977–1989.[CrossRef]
    [Google Scholar]
  22. Lieberman, P. M., O'Hare, P., Hayward, G. S. & Hayward, S. D. ( 1986; ). Promiscuous trans activation of gene expression by an Epstein–Barr virus-encoded early nuclear protein. J Virol 60, 140–148.
    [Google Scholar]
  23. Lukac, D. M., Renne, R., Kirshner, J. R. & Ganem, D. ( 1998; ). Reactivation of Kaposi's sarcoma-associated herpesvirus infection from latency by expression of the ORF 50 transactivator, a homolog of the EBV R protein. Virology 252, 304–312.[CrossRef]
    [Google Scholar]
  24. Lukac, D. M., Kirshner, J. R. & Ganem, D. ( 1999; ). Transcriptional activation by the product of open reading frame 50 of Kaposi's sarcoma-associated herpesvirus is required for lytic viral reactivation in B cells. J Virol 73, 9348–9361.
    [Google Scholar]
  25. Lukac, D. M., Garibyan, L., Kirshner, J. R., Palmeri, D. & Ganem, D. ( 2001; ). DNA binding by Kaposi's sarcoma-associated herpesvirus lytic switch protein is necessary for transcriptional activation of two viral delayed early promoters. J Virol 75, 6786–6799.[CrossRef]
    [Google Scholar]
  26. McMahan, L. & Schaffer, P. A. ( 1990; ). The repressing and enhancing functions of the herpes simplex virus regulatory protein ICP27 map to C-terminal regions and are required to modulate viral gene expression very early in infection. J Virol 64, 3471–3485.
    [Google Scholar]
  27. Mears, W. E. & Rice, S. A. ( 1996; ). The RGG box motif of the herpes simplex virus ICP27 protein mediates an RNA-binding activity and determines in vivo methylation. J Virol 70, 7445–7453.
    [Google Scholar]
  28. Milligan, S., Robinson, M., O'Donnell, E. & Blackbourn, D. J. ( 2004; ). Inflammatory cytokines inhibit KSHV lytic gene transcription in in vitro-infected endothelial cells. J Virol 78, 2591–2596.[CrossRef]
    [Google Scholar]
  29. Moore, P. S. & Chang, Y. ( 2001; ). Molecular virology of Kaposi's sarcoma-associated herpesvirus. Philos Trans R Soc Lond B Biol Sci 356, 499–516.[CrossRef]
    [Google Scholar]
  30. Nicholas, J., Gompels, U. A., Craxton, M. A. & Honess, R. W. ( 1988; ). Conservation of sequence and function between the product of the 52-kilodalton immediate-early gene of herpesvirus saimiri and the BMLF1-encoded transcriptional effector (EB2) of Epstein–Barr virus. J Virol 62, 3250–3257.
    [Google Scholar]
  31. Panagiotidis, C. A., Lium, E. K. & Silverstein, S. J. ( 1997; ). Physical and functional interactions between herpes simplex virus immediate-early proteins ICP4 and ICP27. J Virol 71, 1547–1557.
    [Google Scholar]
  32. Paulose-Murphy, M., Ha, N. K., Xiang, C. & 7 other authors ( 2001; ). Transcription program of human herpesvirus 8 (Kaposi's sarcoma-associated herpesvirus). J Virol 75, 4843–4853.[CrossRef]
    [Google Scholar]
  33. Proudfoot, N. J., Furger, A. & Dye, M. J. ( 2002; ). Integrating mRNA processing with transcription. Cell 108, 501–512.[CrossRef]
    [Google Scholar]
  34. Reed, R. & Hurt, E. ( 2002; ). A conserved mRNA export machinery coupled to pre-mRNA splicing. Cell 108, 523–531.[CrossRef]
    [Google Scholar]
  35. Renne, R., Zhong, W., Herndier, B., McGrath, M., Abbey, N., Kedes, D. & Ganem, D. ( 1996; ). Lytic growth of Kaposi's sarcoma-associated herpesvirus (human herpesvirus 8) in culture. Nat Med 2, 342–346.[CrossRef]
    [Google Scholar]
  36. Rice, S. A. & Knipe, D. M. ( 1988; ). Gene-specific transactivation by herpes simplex virus type 1 alpha protein ICP27. J Virol 62, 3814–3823.
    [Google Scholar]
  37. Sakakibara, S., Ueda, K., Chen, J., Okuno, T. & Yamanishi, K. ( 2001; ). Octamer-binding sequence is a key element for the autoregulation of Kaposi's sarcoma-associated herpesvirus ORF50/Lyta gene expression. J Virol 75, 6894–6900.[CrossRef]
    [Google Scholar]
  38. Sandri-Goldin, R. M. & Mendoza, G. E. ( 1992; ). A herpesvirus regulatory protein appears to act post-transcriptionally by affecting mRNA processing. Genes Dev 6, 848–863.[CrossRef]
    [Google Scholar]
  39. Sarid, R., Olsen, S. J. & Moore, P. S. ( 1999; ). Kaposi's sarcoma-associated herpesvirus: epidemiology, virology, and molecular biology. Adv Virus Res 52, 139–232.
    [Google Scholar]
  40. Schulz, T. F. ( 1998; ). Kaposi's sarcoma-associated herpesvirus (human herpesvirus-8). J Gen Virol 79, 1573–1591.
    [Google Scholar]
  41. Schulz, T. F. ( 1999; ). Epidemiology of Kaposi's sarcoma-associated herpesvirus/human herpesvirus 8. Adv Cancer Res 76, 121–160.
    [Google Scholar]
  42. Seaman, W. T., Ye, D., Wang, R. X., Hale, E. E., Weisse, M. & Quinlivan, E. B. ( 1999; ). Gene expression from the ORF50/K8 region of Kaposi's sarcoma-associated herpesvirus. Virology 263, 436–449.[CrossRef]
    [Google Scholar]
  43. Song, M. J., Brown, H. J., Wu, T. T. & Sun, R. ( 2001; ). Transcription activation of polyadenylated nuclear RNA by RTA in human herpesvirus 8/Kaposi's sarcoma-associated herpesvirus. J Virol 75, 3129–3140.[CrossRef]
    [Google Scholar]
  44. Spengler, M. L., Ruyechan, W. T. & Hay, J. ( 2000; ). Physical interaction between two varicella zoster virus gene regulatory proteins, IE4 and IE62. Virology 272, 375–381.[CrossRef]
    [Google Scholar]
  45. Staskus, K. A., Zhong, W., Gebhard, K. & 8 other authors ( 1997; ). Kaposi's sarcoma-associated herpesvirus gene expression in endothelial (spindle) tumor cells. J Virol 71, 715–719.
    [Google Scholar]
  46. Su, L. & Knipe, D. M. ( 1989; ). Herpes simplex virus alpha protein ICP27 can inhibit or augment viral gene transactivation. Virology 170, 496–504.[CrossRef]
    [Google Scholar]
  47. Sun, R., Lin, S. F., Gradoville, L., Yuan, Y., Zhu, F. & Miller, G. ( 1998; ). A viral gene that activates lytic cycle expression of Kaposi's sarcoma-associated herpesvirus. Proc Natl Acad Sci U S A 95, 10866–10871.[CrossRef]
    [Google Scholar]
  48. Sun, R., Lin, S. F., Staskus, K., Gradoville, L., Grogan, E., Haase, A. & Miller, G. ( 1999; ). Kinetics of Kaposi's sarcoma-associated herpesvirus gene expression. J Virol 73, 2232–2242.
    [Google Scholar]
  49. Wadd, S., Bryant, H., Filhol, O., Scott, J. E., Hsieh, T. Y., Everett, R. D. & Clements, J. B. ( 1999; ). The multifunctional herpes simplex virus IE63 protein interacts with heterogeneous ribonucleoprotein K and with casein kinase 2. J Biol Chem 274, 28991–28998.[CrossRef]
    [Google Scholar]
  50. Wang, S. E., Wu, F. Y., Fujimuro, M., Zong, J., Hayward, S. D. & Hayward, G. S. ( 2003a; ). Role of CCAAT/enhancer-binding protein alpha (C/EBPα) in activation of the Kaposi's sarcoma-associated herpesvirus (KSHV) lytic-cycle replication-associated protein (RAP) promoter in cooperation with the KSHV replication and transcription activator (RTA) and RAP. J Virol 77, 600–623.[CrossRef]
    [Google Scholar]
  51. Wang, S. E., Wu, F. Y., Yu, Y. & Hayward, G. S. ( 2003b; ). CCAAT/enhancer-binding protein-α is induced during the early stages of Kaposi's sarcoma-associated herpesvirus (KSHV) lytic cycle reactivation and together with the KSHV replication and transcription activator (RTA) cooperatively stimulates the viral RTA, MTA, and PAN promoters. J Virol 77, 9590–9612.[CrossRef]
    [Google Scholar]
  52. Wang, S. E., Wu, F. Y., Chen, H., Shamay, M., Zheng, Q. & Hayward, G. S. ( 2004; ). Early activation of the Kaposi's sarcoma-associated herpesvirus RTA, RAP, and MTA promoters by the tetradecanoyl phorbol acetate-induced AP1 pathway. J Virol 78, 4248–4267.[CrossRef]
    [Google Scholar]
  53. Whitehouse, A., Carr, I. M., Griffiths, J. C. & Meredith, D. M. ( 1997; ). The herpesvirus saimiri ORF50 gene, encoding a transcriptional activator homologous to the Epstein–Barr virus R protein, is transcribed from two distinct promoters of different temporal phases. J Virol 71, 2550–2554.
    [Google Scholar]
  54. Whitehouse, A., Cooper, M. & Meredith, D. M. ( 1998; ). The immediate-early gene product encoded by open reading frame 57 of herpesvirus saimiri modulates gene expression at a posttranscriptional level. J Virol 72, 857–861.
    [Google Scholar]
  55. Wu, F. Y., Wang, S. E., Tang, Q. Q. & 7 other authors ( 2003; ). Cell cycle arrest by Kaposi's sarcoma-associated herpesvirus replication-associated protein is mediated at both the transcriptional and posttranslational levels by binding to CCAAT/enhancer-binding protein alpha and p21(CIP-1). J Virol 77, 8893–8914.[CrossRef]
    [Google Scholar]
  56. Zhou, C. & Knipe, D. M. ( 2002; ). Association of herpes simplex virus type 1 ICP8 and ICP27 proteins with cellular RNA polymerase II holoenzyme. J Virol 76, 5893–5904.[CrossRef]
    [Google Scholar]
  57. Zhu, Z. & Schaffer, P. A. ( 1995; ). Intracellular localization of the herpes simplex virus type 1 major transcriptional regulatory protein, ICP4, is affected by ICP27. J Virol 69, 49–59.
    [Google Scholar]
  58. Zhu, F. X., Cusano, T. & Yuan, Y. ( 1999; ). Identification of the immediate-early transcripts of Kaposi's sarcoma-associated herpesvirus. J Virol 73, 5556–5567.
    [Google Scholar]
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