1887

Abstract

Latent membrane protein 2A (LMP2A) of Epstein–Barr virus (EBV) shares protein motifs with the B-cell receptor that play a role in B-cell receptor signalling and has been shown to mimic an activated B-cell receptor by providing a survival signal for mature B cells in transgenic mice. Conversely, LMP2A has been reported not to support but to inhibit B-cell receptor signalling with respect to virus reactivation and to block lytic virus induction after anti-Ig treatment of EBV-infected B cells. To solve this apparent paradox, the role of LMP2A in lytic-cycle induction was re-examined in B cells conditionally immortalized by EBV. It was shown that, in the absence of other stimuli, LMP2A expression alone could lead to induction of the virus lytic cycle. Similarly to B-cell receptor stimulation by anti-Ig treatment, this LMP2A-mediated reactivation was dependent on the mitogen-activated protein kinase pathway and could be inhibited by the viral LMP1. Our data reinforce the notion that LMP2A is a functional homologue of the B-cell receptor, not only with respect to B-cell survival but also with respect to regulation of the lytic cycle.

Loading

Article metrics loading...

/content/journal/jgv/10.1099/vir.0.80440-0
2005-03-01
2019-11-19
Loading full text...

Full text loading...

/deliver/fulltext/jgv/86/3/vir860551.html?itemId=/content/journal/jgv/10.1099/vir.0.80440-0&mimeType=html&fmt=ahah

References

  1. Adler, B., Ashkar, S., Cantor, H. & Weber, G. F. ( 2001; ). Costimulation by extracellular matrix proteins determines the response to TCR ligation. Cell Immunol 210, 30–40.[CrossRef]
    [Google Scholar]
  2. 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 A 99, 437–442.[CrossRef]
    [Google Scholar]
  3. Alber, G., Kim, K.-M., Weiser, P., Riesterer, C., Carsetti, R. & Reth, M. ( 1993; ). Molecular mimicry of the antigen receptor signalling motif by transmembrane proteins of the Epstein–Barr virus and the bovine leukaemia virus. Curr Biol 3, 333–339.[CrossRef]
    [Google Scholar]
  4. Babcock, G. J. & Thorley-Lawson, D. A. ( 2000; ). Tonsillar memory B cells, latently infected with Epstein–Barr virus, express the restricted pattern of latent genes previously found only in Epstein–Barr virus-associated tumors. Proc Natl Acad Sci U S A 97, 12250–12255.[CrossRef]
    [Google Scholar]
  5. Babcock, G. J., Decker, L. L., Volk, M. & Thorley-Lawson, D. A. ( 1998; ). EBV persistence in memory B cells in vivo. Immunity 9, 395–404.[CrossRef]
    [Google Scholar]
  6. Babcock, G. J., Decker, L. L., Freeman, R. B. & Thorley-Lawson, D. A. ( 1999; ). Epstein–Barr virus-infected resting memory B cells, not proliferating lymphoblasts, accumulate in the peripheral blood of immunosuppressed patients. J Exp Med 190, 567–576.[CrossRef]
    [Google Scholar]
  7. Babcock, G. J., Hochberg, D. & Thorley-Lawson, A. D. ( 2000; ). The expression pattern of Epstein–Barr virus latent genes in vivo is dependent upon the differentiation stage of the infected B cell. Immunity 13, 497–506.[CrossRef]
    [Google Scholar]
  8. Beaufils, P., Choquet, D., Mamoun, R. Z. & Malissen, B. ( 1993; ). The (YXXL/I)2 signalling motif found in the cytoplasmic segments of the bovine leukaemia virus envelope protein and Epstein–Barr virus latent membrane protein 2A can elicit early and late lymphocyte activation events. EMBO J 12, 5105–5112.
    [Google Scholar]
  9. Brielmeier, M., Bechet, J. M., Suppmann, S., Conrad, M., Laux, G. & Bornkamm, G. W. ( 2001; ). Cloning of phospholipid hydroperoxide glutathione peroxidase (PHGPx) as an anti-apoptotic and growth promoting gene of Burkitt lymphoma cells. Biofactors 14, 179–190.[CrossRef]
    [Google Scholar]
  10. Caldwell, R. G., Wilson, J. B., Anderson, S. J. & Longnecker, R. ( 1998; ). Epstein–Barr virus LMP2A drives B cell development and survival in the absence of normal B cell receptor signals. Immunity 9, 405–411.[CrossRef]
    [Google Scholar]
  11. Campbell, K. S. ( 1999; ). Signal transduction from the B cell antigen-receptor. Curr Opin Immunol 11, 256–264.[CrossRef]
    [Google Scholar]
  12. Chen, S.-Y., Lu, J., Shih, Y.-C. & Tsai, C.-H. ( 2002; ). Epstein–Barr virus latent membrane protein 2A regulates c-Jun protein through extracellular signal-regulated kinase. J Virol 76, 9556–9561.[CrossRef]
    [Google Scholar]
  13. Decker, L. L., Klaman, L. D. & Thorley-Lawson, D. A. ( 1996; ). Detection of the latent form of Epstein–Barr virus DNA in the peripheral blood of healthy individuals. J Virol 70, 3286–3289.
    [Google Scholar]
  14. Dykstra, M. L., Longnecker, R. & Pierce, S. K. ( 2001; ). Epstein–Barr virus coopts lipid rafts to block the signaling and antigen transport functions of the BCR. Immunity 14, 57–67.[CrossRef]
    [Google Scholar]
  15. Fenton, M. & Sinclair, A. J. ( 1999; ). Divergent requirements for the MAPKERK signal transduction pathway during initial virus infection of quiescent primary B cells and disruption of Epstein–Barr virus latency by phorbol esters. J Virol 73, 8913–8916.
    [Google Scholar]
  16. Fruehling, S., Lee, S., Herrold, R., Frech, B., Laux, G., Kremmer, E., Grässer, F. A. & Longnecker, R. ( 1996; ). Identification of latent membrane protein 2A (LMP2A) domains essential for the LMP2A dominant-negative effect on B-lymphocyte surface immunoglobulin signal transduction. J Virol 70, 6216–6226.
    [Google Scholar]
  17. Hergenhahn, M., Soto, U., Weninger, A., Polack, A., Hsu, C.-H., Cheng, A.-L. & Rosl, F. ( 2002; ). The chemopreventive compound curcumin is an efficient inhibitor of Epstein–Barr virus BZLF1 transcription in Raji DR-LUC cells. Mol Carcinog 33, 137–145.[CrossRef]
    [Google Scholar]
  18. 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 A 98, 4675–4680.[CrossRef]
    [Google Scholar]
  19. Hinuma, Y., Konn, M., Yamaguchi, J., Wudarski, D. J., Blakeslee, J. R. J. & Grace, J. T. J. ( 1967; ). Immunofluorescence and herpes-type virus particles in the P3HR-1 Burkitt lymphoma cell line. J Virol 1, 1045–1051.
    [Google Scholar]
  20. Hochberg, D., Middeldorp, J. M., Catalina, M., Sullivan, J. L., Luzuriaga, K. & Thorley-Lawson, D. A. ( 2004a; ). Demonstration of the Burkitt's lymphoma Epstein–Barr virus phenotype in dividing latently infected memory cells in vivo. Proc Natl Acad Sci U S A 101, 239–244.[CrossRef]
    [Google Scholar]
  21. Hochberg, D., Souza, T., Catalina, M., Sullivan, J. L., Luzuriaga, K. & Thorley-Lawson, D. A. ( 2004b; ). Acute infection with Epstein–Barr virus targets and overwhelms the peripheral memory B-cell compartment with resting, latently infected cells. J Virol 78, 5194–5204.[CrossRef]
    [Google Scholar]
  22. Kaykas, A. & Sugden, B. ( 2000; ). The amino-terminus and membrane-spanning domains of LMP-1 inhibit cell proliferation. Oncogene 19, 1400–1410.[CrossRef]
    [Google Scholar]
  23. Kempkes, B., Spitkovsky, D., Jansen-Durr, P., Ellwart, J. W., Kremmer, E., Delecluse, H. J., Rottenberger, C., Bornkamm, G. W. & Hammerschmidt, W. ( 1995; ). B-cell proliferation and induction of early G1-regulating proteins by Epstein–Barr virus mutants conditional for EBNA2. EMBO J 14, 88–96.
    [Google Scholar]
  24. Kempkes, B., Zimber-Strobl, U., Eissner, G., Pawlita, M., Falk, M., Hammerschmidt, W. & Bornkamm, G. W. ( 1996a; ). Epstein–Barr virus nuclear antigen 2 (EBNA2)–oestrogen receptor fusion proteins complement the EBNA2-deficient Epstein–Barr virus strain P3HR1 in transformation of primary B cells but suppress growth of human B cell lymphoma lines. J Gen Virol 77, 227–237.[CrossRef]
    [Google Scholar]
  25. Kempkes, B., Zimber-Strobl, U., Eissner, G., Pawlita, M., Falk, M., Hammerschmidt, W. & Bornkamm, G. W. ( 1996b; ). Epstein–Barr virus nuclear antigen 2 (EBNA2)-oestrogen receptor fusion proteins complement the EBNA2-deficient Epstein–Barr virus strain P3HR1 in transformation of primary B cells but suppress growth of human B cell lymphoma lines. J Gen Virol 77, 227–237.[CrossRef]
    [Google Scholar]
  26. Kieser, A., Kaiser, C. & Hammerschmidt, W. ( 1999; ). LMP1 signal transduction differs substantially from TNF receptor 1 signaling in the molecular functions of TRADD and TRAF2. EMBO J 18, 2511–2521.[CrossRef]
    [Google Scholar]
  27. Konishi, K., Maruo, S., Kato, H. & Takada, K. ( 2001; ). Role of Epstein–Barr virus-encoded latent membrane protein 2A on virus-induced immortalization and virus activation. J Gen Virol 82, 1451–1456.
    [Google Scholar]
  28. Lam, K. M., Syed, N., Whittle, H. & Crawford, D. ( 1991; ). Circulating Epstein–Barr virus-carrying B cells in acute malaria. Lancet 337, 876–878.[CrossRef]
    [Google Scholar]
  29. Laux, G., Freese, U. K. & Bornkamm, G. W. ( 1985; ). Structure and evolution of two related transcription units of Epstein–Barr virus carrying small tandem repeats. J Virol 56, 987–995.
    [Google Scholar]
  30. Laux, G., Perricaudet, M. & Farrell, P. J. ( 1988; ). A spliced Epstein–Barr virus gene expressed in immortalized lymphocytes is created by circularization of the linear viral genome. EMBO J 7, 769–774.
    [Google Scholar]
  31. Laux, G., Economou, A. & Farrell, P. J. ( 1989; ). The terminal protein gene 2 of Epstein–Barr virus is transcribed from a bidirectional latent promoter region. J Gen Virol 70, 3079–3084.[CrossRef]
    [Google Scholar]
  32. Longnecker, R. ( 2000; ). Epstein–Barr virus latency: LMP2, a regulator or means for Epstein–Barr virus persistence? Adv Cancer Res 79, 175–200.
    [Google Scholar]
  33. Miller, C. L., Longnecker, R. & Kieff, E. ( 1993; ). Epstein–Barr virus latent membrane protein 2A blocks calcium mobilization in B lymphocytes. J Virol 67, 3087–3094.
    [Google Scholar]
  34. Miller, C. L., Lee, J. H., Kieff, E. & Longnecker, R. ( 1994; ). An integral membrane protein (LMP2) blocks reactivation of Epstein–Barr virus from latency following surface immunoglobulin crosslinking. Proc Natl Acad Sci U S A 91, 772–776.[CrossRef]
    [Google Scholar]
  35. Miller, C. L., Burkhardt, A. L., Lee, J. H., Stealey, B., Longnecker, R., Bolen, J. B. & Kieff, E. ( 1995; ). Integral membrane protein 2 of Epstein–Barr virus regulates reactivation from latency through dominant negative effects on protein-tyrosine kinases. Immunity 2, 155–166.[CrossRef]
    [Google Scholar]
  36. Miyashita, E. M., Yang, B., Babcock, G. J. & Thorley-Lawson, D. A. ( 1997; ). Identification of the site of Epstein–Barr virus persistence in vivo as a resting B cell. J Virol 71, 4882–4891.
    [Google Scholar]
  37. Polack, A., Laux, G., Hergenhahn, M., Kloz, U., Roeser, H., Hecker, E. & Bornkamm, G. W. ( 1992; ). Short-term assays for detection of conditional cancerogens. I. Construction of DR-CAT Raji cells and some of their characteristics as tester cells. Int J Cancer 50, 611–616.[CrossRef]
    [Google Scholar]
  38. Qu, L. & Rowe, D. T. ( 1992; ). Epstein–Barr virus latent gene expression in uncultured peripheral blood lymphocytes. J Virol 66, 3715–3724.
    [Google Scholar]
  39. Rabson, M., Heston, L. & Miller, G. ( 1983; ). Identification of a rare Epstein–Barr virus variant that enhances early antigen expression in Raji cells. Proc Natl Acad Sci U S A 80, 2762–2766.[CrossRef]
    [Google Scholar]
  40. Rickinson, A. B. & Kieff, E. ( 2001; ). Epstein–Barr virus. In Fields Virology, 4th edn, pp. 2575–2627. Edited by D. M. Knipe, P. M. Howley, D. E. Griffin, M. A. Martin, R. A. Lamb, B. Roizman & S. E. Straus. Philadelphia: Lippincott Williams & Wilkins.
  41. Rowe, D. T., Hall, L., Joab, I. & Laux, G. ( 1990; ). Identification of the Epstein–Barr virus terminal protein gene products in latently infected lymphocytes. J Virol 64, 2866–2875.
    [Google Scholar]
  42. Sugden, B., Marsh, K. & Yates, J. ( 1985; ). A vector that replicates as a plasmid and can be efficiently selected in B-lymphoblasts transformed by Epstein–Barr virus. Mol Cell Biol 5, 410–413.
    [Google Scholar]
  43. Takada, K. ( 1984; ). Cross-linking of cell surface immunoglobulins induces Epstein–Barr virus in Burkitt lymphoma lines. Int J Cancer 33, 27–32.[CrossRef]
    [Google Scholar]
  44. Thorley-Lawson, D. A. ( 2001; ). Epstein–Barr virus: exploiting the immune system. Nat Rev Immunol 1, 75–82.[CrossRef]
    [Google Scholar]
  45. Tierney, R. J., Steven, N., Young, L. S. & Rickinson, A. B. ( 1994; ). Epstein–Barr virus latency in blood mononuclear cells: analysis of viral gene transcription during primary infection and in the carrier state. J Virol 68, 7374–7385.
    [Google Scholar]
  46. Tovey, M., Lenoir, G. & Lours-Begon, J. ( 1978; ). Activation of latent Epstein–Barr virus by antibody to human IgM. Nature 276, 270–272.[CrossRef]
    [Google Scholar]
  47. Zimber-Strobl, U., Suentzenich, K. O., Laux, G., Eick, D., Cordier, M., Calendar, A., Billaud, M., Lenoir, G. M. & Bornkamm, G. W. ( 1991; ). Epstein–Barr virus nuclear antigen 2 activated transcription of the terminal protein gene. J Virol 65, 415–424.
    [Google Scholar]
  48. 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 J 15, 7070–7078.
    [Google Scholar]
http://instance.metastore.ingenta.com/content/journal/jgv/10.1099/vir.0.80440-0
Loading
/content/journal/jgv/10.1099/vir.0.80440-0
Loading

Data & Media loading...

Most Cited This Month

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