1887

Abstract

Epstein–Barr virus (EBV) is a human herpesvirus associated with a number of malignancies. EBV establishes a latent infection in human B cells , and infected lymphoblastoid cells proliferate indefinitely as a result of virus activation of cellular signalling pathways. Latently infected cells express a viral oncoprotein called the latent membrane protein-1 (LMP-1). LMP-1 signals both proliferative and survival signals to the infected B cell. The switch from latency to lytic replication is associated with upregulation of an N-terminally truncated LMP-1, called lytic LMP-1 (lyLMP-1). To understand better the relationship between LMP-1 protein function and the virus life cycle, LMP-1 and lyLMP-1 were precisely localized in infected B cells. Immunoelectron microscopy of latently infected cells revealed LMP-1 localized in discrete patches in the plasma membrane. Unexpectedly, immunogold-labelled LMP-1 was found in vesicles budding from the plasma membrane into the extracellular space and in small membrane vesicles accumulating in conditioned medium from infected cells. LyLMP-1 immunolabelling was observed only in B95-8 cells harbouring detectable intracellular virus particles and was abundant in the nuclear membrane early, and in the plasma membrane late, following lytic cycle induction. LyLMP-1 immunoreactivity was also observed at sites of virus budding and associated with intracellular virions, suggesting that lyLMP-1 might be incorporated into cytoplasmic virions when budding through the nuclear membrane.

Loading

Article metrics loading...

/content/journal/jgv/10.1099/vir.0.19156-0
2003-08-01
2020-05-25
Loading full text...

Full text loading...

/deliver/fulltext/jgv/84/8/vir841997.html?itemId=/content/journal/jgv/10.1099/vir.0.19156-0&mimeType=html&fmt=ahah

References

  1. Adler B., Schaadt E., Kempkes B., Zimber-Strobl U., Baier B., Bornkamm G. W.. 2002; Control of Epstein–Barr virus reactivation by activated CD40 and viral latent membrane protein 1. Proc Natl Acad Sci U S A99:437–442
    [Google Scholar]
  2. Baichwal V. R., Sugden B.. 1987; Posttranslational processing of an Epstein–Barr virus-encoded membrane protein expressed in cells transformed by Epstein–Barr virus. J Virol61:866–875
    [Google Scholar]
  3. Baichwal V. R., Sugden B.. 1989; The multiple membrane-spanning segments of the BNLF-1 oncogene from Epstein–Barr virus are required for transformation. Oncogene4:67–74
    [Google Scholar]
  4. Cannon M. J., Pisa P., Fox R. I., Cooper N. R.. 1990; Epstein–Barr virus induces aggressive lymphoproliferative disorders of human B cell origin in SCID/hu chimeric mice. J Clin Invest85:1333–1337
    [Google Scholar]
  5. Coffin W. F. III, Erickson K. D., Hoedt-Miller M., Martin J. M.. 2001; The cytoplasmic amino-terminus of the latent membrane protein-1 of Epstein–Barr virus: relationship between transmembrane orientation and effector functions of the carboxy-terminus and transmembrane domain. Oncogene20:5313–5330
    [Google Scholar]
  6. Cohen J. I.. 1991; Epstein–Barr virus lymphoproliferative disease associated with acquired immunodeficiency. Medicine70:137–160
    [Google Scholar]
  7. Dukers D. F., Meij P., Vervoort M. B. H. J., Vos W., Scheper R. J., Meijer C. J. L. M., Bloemena E., Middeldorp J. M.. 2000; Direct immunosuppressive effects of EBV-encoded latent membrane protein 1. J Immunol165:663–670
    [Google Scholar]
  8. Eliopoulos A. G., Rickinson A. B.. 1998; Epstein–Barr virus: LMP1 masquerades as an active receptor. Curr Biol8:R196–R198
    [Google Scholar]
  9. Erickson K. D., Martin J. M.. 1997; Early detection of the lytic LMP-1 protein in EBV-infected B-cells suggests its presence in the virion. Virology234:1–13
    [Google Scholar]
  10. Erickson K. D., Martin J. M.. 2000; The late lytic LMP-1 protein of Epstein–Barr virus can negatively regulate LMP-1 signaling. J Virol74:1057–1060
    [Google Scholar]
  11. Escola J., Kleijmeer M. J., Stoorvogel W., Griffith J. M., Yoshie O., Geuze H. J.. 1998; Selective enrichment of tetraspan proteins on the internal vesicles of multivesicular endosomes and on exosomes secreted by human B-lymphocytes. J Biol Chem273:20121–20127
    [Google Scholar]
  12. Fennewald S., van Santen V., Kieff E.. 1984; Nucleotide sequence of an mRNA transcribed in latent growth-transforming virus infection indicates that it may encode a membrane protein. J Virol51:411–419
    [Google Scholar]
  13. Floettmann J. E., Ward K., Rickinson A. B., Rowe M.. 1996; Cytostatic effect of Epstein–Barr virus latent membrane protein-1 analyzed using tetracycline-regulated expression in B cell lines. Virology223:29–40
    [Google Scholar]
  14. Garnier J. L., Berger F., Betuel H.. 7 other authors 1989; Epstein–Barr virus associated lymphoproliferative diseases (B cell lymphoma) after transplantation. Nephrol Dial Transplant4:818–823
    [Google Scholar]
  15. Giddings T. H. Jr, O'Toole E. T., Morphew M., Mastronarde D. N., McIntosh J. R., Winey M.. 2001; Using rapid freeze and freeze-substitution for the preparation of yeast cells for electron microscopy and three-dimensional analysis. Methods Cell Biol67:27–42
    [Google Scholar]
  16. Gong M., Kieff E.. 1990; Intracellular trafficking of two major Epstein–Barr virus glycoproteins, gp350/220 and gp110. J Virol64:1507–1516
    [Google Scholar]
  17. Hammerschmidt W., Sugden B., Baichwal V. R.. 1989; The transforming domain alone of the latent membrane protein of Epstein–Barr virus is toxic to cells when expressed at high levels. J Virol63:2469–2475
    [Google Scholar]
  18. Henle G., Henle W., Diehl V.. 1968; Relation of Burkitt's tumor associated herpes-type virus to infectious mononucleosis. Proc Natl Acad Sci U S A59:94–101
    [Google Scholar]
  19. Higuchi M., Izumi K. M., Kieff E.. 2001; Epstein–Barr virus latent-infection membrane proteins are palmitoylated and raft-associated: protein 1 binds to the cytoskeleton through TNF receptor cytoplasmic factors. Proc Natl Acad Sci U S A98:4675–4680
    [Google Scholar]
  20. Ho M., Jaffe R., Miller G.. 7 other authors 1988; The frequency of Epstein–Barr virus infection and associated lymphoproliferative syndrome after transplantation and its manifestations in children. Transplantation45:719–727
    [Google Scholar]
  21. Hudson G. S., Farrell P. J., Barrell B. G.. 1985; Two related but differentially expressed potential membrane proteins encoded by the Eco RI Dhet region of Epstein–Barr virus B95-8. J Virol53:528–535
    [Google Scholar]
  22. Huen D. S., Henderson S. A., Croom-Carter D., Rowe M.. 1995; The Epstein–Barr virus latent membrane protein-1 (LMP1) mediates activation of NF κ B and cell surface phenotype via two effector regions in its carboxy-terminal cytoplasmic domain. Oncogene10:549–560
    [Google Scholar]
  23. Izumi K. M., Kaye K. M., Kieff E. D.. 1997; The Epstein–Barr virus LMP1 amino acid sequence that engages tumor necrosis factor receptor associated factors is critical for primary B lymphocyte growth transformation. Proc Natl Acad Sci U S A94:1447–1452
    [Google Scholar]
  24. Kavathas P., Bach F. H., DeMars R.. 1980; Gamma ray-induced loss of expression of HLA and glyoxylase I alleles in lymphoblastoid cells. Proc Natl Acad Sci U S A77:4251–4255
    [Google Scholar]
  25. Kaye K. M., Izumi K. M., Kieff E.. 1993; Epstein–Barr virus latent membrane protein 1 is essential for B-lymphocyte growth transformation. Proc Natl Acad Sci U S A90:9150–9154
    [Google Scholar]
  26. Kaykas A., Sugden B.. 2000; The amino-terminus and membrane-spanning domains of LMP-1 inhibit cell proliferation. Oncogene19:1400–1410
    [Google Scholar]
  27. Kaykas A., Worringer K., Sugden B.. 2001; CD40 and LMP-1 both signal from lipid rafts but LMP-1 assembles a distinct, more efficient signaling complex. EMBO J20:2641–2654
    [Google Scholar]
  28. Kilger E., Kieser A., Baumann M., Hammerschmidt W.. 1998; Epstein–Barr virus-mediated B-cell proliferation is dependent upon latent membrane protein 1, which simulates an activated CD40 receptor. EMBO J17:1700–1709
    [Google Scholar]
  29. Liebowitz D., Wang D., Kieff E.. 1986; Orientation and patching of the latent infection membrane protein encoded by Epstein–Barr virus. J Virol58:233–237
    [Google Scholar]
  30. Mann K. P., Staunton D., Thorley-Lawson D.. 1985; Epstein–Barr virus-encoded protein found in plasma membranes of transformed cells. J Virol55:710–720
    [Google Scholar]
  31. Miller G.. 1985; Epstein–Barr virus. In Virology , 1 edn. pp 563–589 Edited by Fields B. N.. New York: Raven Press;
    [Google Scholar]
  32. Miller G.. 1989; The switch between EBV latency and replication. Yale J Biol Med62:205–213
    [Google Scholar]
  33. Miller G., Lipman M.. 1973; Release of infectious Epstein–Barr virus by transformed marmoset leukocytes. Proc Natl Acad Sci U S A70:190–194
    [Google Scholar]
  34. Miller G., Shope T., Lisco H., Stitt D., Lipman M.. 1972; Epstein–Barr virus: transformation, cytopathic changes, and viral antigens in squirrel monkey and marmoset leukocytes. Proc Natl Acad Sci U S A69:383–387
    [Google Scholar]
  35. Mitchell T., Sugden B.. 1995; Stimulation of NF κ B-mediated transcription by mutant derivatives of the latent membrane protein of Epstein–Barr virus. J Virol69:2968–2976
    [Google Scholar]
  36. Niederman J. C., McCollum R. W., Henle G., Henle W.. 1968; Infectious mononucleosis. JAMA203:139–143
    [Google Scholar]
  37. Prince S., Keating S., Fielding C., Brennan P., Floettmann E., Rowe M.. 2002; Latent membrane protein 1 inhibits Epstein–Barr virus lytic cycle induction and progress by different mechanisms. J Virol77:5000–5007
    [Google Scholar]
  38. Raposo G., Nijman H. W., Stoorvogel W., Leijendekker R., Harding C. V., Melief C. J. M., Geuze H. J.. 1996; B lymphocytes secrete antigen-presenting vesicles. J Exp Med183:1161–1172
    [Google Scholar]
  39. Steven A., Spear P. G.. 1997; Herpesvirus capsid assembly and envelopment. In Structural Biology of Viruses pp 312–351 Edited by Chiu W., Burnett W., Garcea R. L.. New York: Oxford University Press;
    [Google Scholar]
  40. Sugden B.. 1982; Epstein–Barr virus: a human pathogen inducing lymphoproliferation in vivo and in vitro . Rev Infect Dis4:1048–1061
    [Google Scholar]
  41. Sugden B.. 1989; An intricate route to immortality. Cell57:5–7
    [Google Scholar]
  42. Sugden B., Mark W.. 1977; Clonal transformation of adult human leukocytes by Epstein–Barr virus. J Virol23:503–508
    [Google Scholar]
  43. Torrisi M. R., Cirone M., Pavan A., Zompetta C., Barile G., Frati L., Faggioni A.. 1989; Localization of Epstein–Barr virus envelope glycoproteins on the inner nuclear membrane of virus-producing cells. J Virol63:828–832
    [Google Scholar]
  44. Wang D., Liebowitz D., Kieff E.. 1988a; The truncated form of the Epstein–Barr virus latent-infection membrane protein expressed in virus replication does not transform rodent fibroblasts. J Virol62:2337–2346
    [Google Scholar]
  45. Wang D., Liebowitz D., Wang F., Gregory C., Rickinson A., Larson R., Springer T., Kieff E.. 1988b; Epstein–Barr virus latent infection membrane protein alters the human B-lymphocyte phenotype: deletion of the amino terminus abolishes activity. J Virol62:4173–4184
    [Google Scholar]
  46. Wild P., Schraner E. M., Cantieni D., Loepfe E., Walther P., Muller M., Engels M.. 2002; The significance of the Golgi complex in envelopment of bovine herpesvirus 1 (BHV-1) as revealed by cryobased electron microscopy. Micron33:327–337
    [Google Scholar]
  47. Zimber-Strobl U., Kempkes B., Marschall G., Zeidler R., Van Kooten C., Banchereau J., Bornkamm G. W., Hammerschmidt W.. 1996; Epstein–Barr virus latent membrane protein (LMP1) is not sufficient to maintain proliferation of B cells but both it and activated CD40 can prolong their survival. EMBO J15:7070–7078
    [Google Scholar]
http://instance.metastore.ingenta.com/content/journal/jgv/10.1099/vir.0.19156-0
Loading
/content/journal/jgv/10.1099/vir.0.19156-0
Loading

Data & Media loading...

Most cited this month Most Cited RSS feed

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