1887

Abstract

Latent membrane protein 2A (LMP2A) of Epstein–Barr virus (EBV) provides developmental and survival signals that mimic those of a B-cell receptor (BCR). Expression of LMP2A during B-cell development results in the ability of B cells to exit the bone marrow in the absence of a BCR and persist in the periphery, where they would normally undergo apoptosis. This study extends the current knowledge of LMP2A function by examining the growth properties of bone marrow B cells from TgE LMP2A mice. Despite the lack of pre-BCR expression, bone marrow B cells from TgE LMP2A mice proliferate and survive in low concentrations of interleukin 7, similar to wild-type cells. Constitutive phosphorylation of ERK/MAPK and PI3K/Akt in TgE LMP2A bone marrow B cells is also reminiscent of signalling through the pre-BCR, altogether demonstrating that LMP2A provides a pre-BCR-like signal to developing B cells.

Loading

Article metrics loading...

/content/journal/jgv/10.1099/vir.0.2008/001461-0
2008-07-01
2019-11-14
Loading full text...

Full text loading...

/deliver/fulltext/jgv/89/7/1563.html?itemId=/content/journal/jgv/10.1099/vir.0.2008/001461-0&mimeType=html&fmt=ahah

References

  1. Bannish, G., Fuentes-Panana, E. M., Cambier, J. C., Pear, W. S. & Monroe, J. G. ( 2001; ). Ligand-independent signaling functions for the B lymphocyte antigen receptor and their role in positive selection during B lymphopoiesis. J Exp Med 194, 1583–1596.[CrossRef]
    [Google Scholar]
  2. Bell, A. I., Groves, K., Kelly, G. L., Croom-Carter, D., Hui, E., Chan, A. T. & Rickinson, A. B. ( 2006; ). Analysis of Epstein–Barr virus latent gene expression in endemic Burkitt's lymphoma and nasopharyngeal carcinoma tumour cells by using quantitative real-time PCR assays. J Gen Virol 87, 2885–2890.[CrossRef]
    [Google Scholar]
  3. Burkhardt, A. L., Bolen, J. B., Kieff, E. & Longnecker, R. ( 1992; ). An Epstein-Barr virus transformation-associated membrane protein interacts with src family tyrosine kinases. J Virol 66, 5161–5167.
    [Google Scholar]
  4. 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]
  5. Caldwell, R. G., Brown, R. C. & Longnecker, R. ( 2000; ). Epstein-Barr virus LMP2A-induced B-cell survival in two unique classes of EmuLMP2A transgenic mice. J Virol 74, 1101–1113.[CrossRef]
    [Google Scholar]
  6. 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]
  7. Corcoran, A. E., Smart, F. M., Cowling, R. J., Crompton, T., Owen, M. J. & Venkitaraman, A. R. ( 1996; ). The interleukin-7 receptor alpha chain transmits distinct signals for proliferation and differentiation during B lymphopoiesis. EMBO J 15, 1924–1932.
    [Google Scholar]
  8. Corfe, S. A., Gray, A. P. & Paige, C. J. ( 2007; ). Generation and characterization of stromal cell independent IL-7 dependent B cell lines. J Immunol Methods 325, 9–19.[CrossRef]
    [Google Scholar]
  9. Era, T., Ogawa, M., Nishikawa, S., Okamoto, M., Honjo, T., Akagi, K., Miyazaki, J. & Yamamura, K. ( 1991; ). Differentiation of growth signal requirement of B lymphocyte precursor is directed by expression of immunoglobulin. EMBO J 10, 337–342.
    [Google Scholar]
  10. Fang, W., Mueller, D. L., Pennell, C. A., Rivard, J. J., Li, Y. S., Hardy, R. R., Schlissel, M. S. & Behrens, T. W. ( 1996; ). Frequent aberrant immunoglobulin gene rearrangements in pro-B cells revealed by a bcl-xL transgene. Immunity 4, 291–299.[CrossRef]
    [Google Scholar]
  11. Fleming, H. E. & Paige, C. J. ( 2001; ). Pre-B cell receptor signaling mediates selective response to IL-7 at the pro-B to pre-B cell transition via an ERK/MAP kinase-dependent pathway. Immunity 15, 521–531.[CrossRef]
    [Google Scholar]
  12. Fleming, H. E. & Paige, C. J. ( 2002; ). Cooperation between IL-7 and the pre-B cell receptor: a key to B cell selection. Semin Immunol 14, 423–430.[CrossRef]
    [Google Scholar]
  13. Fruehling, S. & Longnecker, R. ( 1997; ). The immunoreceptor tyrosine-based activation motif of Epstein-Barr virus LMP2A is essential for blocking BCR-mediated signal transduction. Virology 235, 241–251.[CrossRef]
    [Google Scholar]
  14. Fruehling, S., Lee, S. K., Herrold, R., Frech, B., Laux, G., Kremmer, E., Grasser, 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]
  15. Fruehling, S., Swart, R., Dolwick, K. M., Kremmer, E. & Longnecker, R. ( 1998; ). Tyrosine 112 of latent membrane protein 2A is essential for protein tyrosine kinase loading and regulation of Epstein-Barr virus latency. J Virol 72, 7796–7806.
    [Google Scholar]
  16. Fuentes-Panana, E. M., Bannish, G., Shah, N. & Monroe, J. G. ( 2004; ). Basal Igα/Igβ signals trigger the coordinated initiation of pre-B cell antigen receptor-dependent processes. J Immunol 173, 1000–1011.[CrossRef]
    [Google Scholar]
  17. Fukuda, M. & Longnecker, R. ( 2005; ). Epstein-Barr virus (EBV) latent membrane protein 2A regulates B-cell receptor-induced apoptosis and EBV reactivation through tyrosine phosphorylation. J Virol 79, 8655–8660.[CrossRef]
    [Google Scholar]
  18. Hardy, R. R., Carmack, C. E., Shinton, S. A., Kemp, J. D. & Hayakawa, K. ( 1991; ). Resolution and characterization of pro-B and pre-pro-B cell stages in normal mouse bone marrow. J Exp Med 173, 1213–1225.[CrossRef]
    [Google Scholar]
  19. Ikeda, M. & Longnecker, R. ( 2005; ). Pre-B-cell colony formation assay. Methods Mol Biol 292, 279–284.
    [Google Scholar]
  20. Jacob, A., Cooney, D., Pradhan, M. & Coggeshall, K. M. ( 2002; ). Convergence of signaling pathways on the activation of ERK in B cells. J Biol Chem 277, 23420–23426.[CrossRef]
    [Google Scholar]
  21. Kieff, E. D. & Rickinson, A. B. ( 2007; ). Epstein-Barr virus and its replication. In Fields Virology, 5th edn, pp. 2603–2654. Edited by P. M. H. David, M. Knipe, D. E. Griffin, R. A. Lamb, M. A. Martin, B. Roizman & S. E. Straus. Philadelphia, PA: Lippincott-Raven Publishers.
  22. 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]
  23. 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]
  24. Longnecker, R., Druker, B., Roberts, T. M. & Kieff, E. ( 1991; ). An Epstein-Barr virus protein associated with cell growth transformation interacts with a tyrosine kinase. J Virol 65, 3681–3692.
    [Google Scholar]
  25. Lu, J., Lin, W. H., Chen, S. Y., Longnecker, R., Tsai, S. C., Chen, C. L. & Tsai, C. H. ( 2006; ). Syk tyrosine kinase mediates Epstein-Barr virus latent membrane protein 2A-induced cell migration in epithelial cells. J Biol Chem 281, 8806–8814.[CrossRef]
    [Google Scholar]
  26. Mancao, C. & Hammerschmidt, W. ( 2007; ). Epstein-Barr virus latent membrane protein 2A is a B-cell receptor mimic and essential for B-cell survival. Blood 110, 3715–3721.[CrossRef]
    [Google Scholar]
  27. Marshall, A. J., Fleming, H. E., Wu, G. E. & Paige, C. J. ( 1998; ). Modulation of the IL-7 dose-response threshold during pro-B cell differentiation is dependent on pre-B cell receptor expression. J Immunol 161, 6038–6045.
    [Google Scholar]
  28. 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]
  29. 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]
  30. 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]
  31. Monroe, J. G. ( 2006; ). ITAM-mediated tonic signalling through pre-BCR and BCR complexes. Nat Rev Immunol 6, 283–294.[CrossRef]
    [Google Scholar]
  32. Morrison, J. A., Klingelhutz, A. J. & Raab-Traub, N. ( 2003; ). Epstein-Barr virus latent membrane protein 2A activates β-catenin signaling in epithelial cells. J Virol 77, 12276–12284.[CrossRef]
    [Google Scholar]
  33. Panousis, C. G. & Rowe, D. T. ( 1997; ). Epstein-Barr virus latent membrane protein 2 associates with and is a substrate for mitogen-activated protein kinase. J Virol 71, 4752–4760.
    [Google Scholar]
  34. Portis, T. & Longnecker, R. ( 2004; ). Epstein-Barr virus (EBV) LMP2A mediates B-lymphocyte survival through constitutive activation of the Ras/PI3K/Akt pathway. Oncogene 23, 8619–8628.[CrossRef]
    [Google Scholar]
  35. Portis, T., Dyck, P. & Longnecker, R. ( 2003; ). Epstein-Barr Virus (EBV) LMP2A induces alterations in gene transcription similar to those observed in Reed-Sternberg cells of Hodgkin lymphoma. Blood 102, 4166–4178.[CrossRef]
    [Google Scholar]
  36. Rechsteiner, M. P., Berger, C., Weber, M., Sigrist, J. A., Nadal, D. & Bernasconi, M. ( 2007; ). Silencing of latent membrane protein 2B reduces susceptibility to activation of lytic Epstein–Barr virus in Burkitt's lymphoma Akata cells. J Gen Virol 88, 1454–1459.[CrossRef]
    [Google Scholar]
  37. Rickinson, A. B. & Kieff, E. ( 2007; ). Epstein-Barr virus. In Fields Virology, 5th edn, pp. 2655–2700. Edited by P. M. H. David, M. Knipe, D. E. Griffin, R. A. Lamb, M. A. Martin, B. Roizman & S. E. Straus. Philadelphia, PA: Lippincott-Raven Publishers.
  38. Scholle, F., Bendt, K. M. & Raab-Traub, N. ( 2000; ). Epstein-Barr virus LMP2A transforms epithelial cells, inhibits cell differentiation, and activates Akt. J Virol 74, 10681–10689.[CrossRef]
    [Google Scholar]
  39. Shaffer, A. L. & Schlissel, M. S. ( 1997; ). A truncated heavy chain protein relieves the requirement for surrogate light chains in early B cell development. J Immunol 159, 1265–1275.
    [Google Scholar]
  40. Steelman, L. S., Pohnert, S. C., Shelton, J. G., Franklin, R. A., Bertrand, F. E. & McCubrey, J. A. ( 2004; ). JAK/STAT, Raf/MEK/ERK, PI3K/Akt and BCR-ABL in cell cycle progression and leukemogenesis. Leukemia 18, 189–218.[CrossRef]
    [Google Scholar]
  41. Swanson-Mungerson, M. A., Caldwell, R. G., Bultema, R. & Longnecker, R. ( 2005; ). Epstein-Barr virus LMP2A alters in vivo and in vitro models of B-cell anergy, but not deletion, in response to autoantigen. J Virol 79, 7355–7362.[CrossRef]
    [Google Scholar]
  42. Swanson-Mungerson, M., Bultema, R. & Longnecker, R. ( 2006; ). Epstein-Barr virus LMP2A enhances B-cell responses in vivo and in vitro. J Virol 80, 6764–6770.[CrossRef]
    [Google Scholar]
  43. Tao, Q., Robertson, K. D., Manns, A., Hildesheim, A. & Ambinder, R. F. ( 1998; ). Epstein-Barr virus (EBV) in endemic Burkitt's lymphoma: molecular analysis of primary tumor tissue. Blood 91, 1373–1381.
    [Google Scholar]
  44. Teh, Y. M. & Neuberger, M. S. ( 1997; ). The immunoglobulin (Ig)α and Igβ cytoplasmic domains are independently sufficient to signal B cell maturation and activation in transgenic mice. J Exp Med 185, 1753–1758.[CrossRef]
    [Google Scholar]
  45. Thorley-Lawson, D. A. ( 2005; ). EBV the prototypical human tumor virus–just how bad is it? J Allergy Clin Immunol 116, 251–261.[CrossRef]
    [Google Scholar]
  46. Thorley-Lawson, D. A. & Gross, A. ( 2004; ). Persistence of the Epstein-Barr virus and the origins of associated lymphomas. N Engl J Med 350, 1328–1337.[CrossRef]
    [Google Scholar]
  47. Xue, S. A., Labrecque, L. G., Lu, Q. L., Ong, S. K., Lampert, I. A., Kazembe, P., Molyneux, E., Broadhead, R. L., Borgstein, E. & Griffin, B. E. ( 2002; ). Promiscuous expression of Epstein-Barr virus genes in Burkitt's lymphoma from the central African country Malawi. Int J Cancer 99, 635–643.[CrossRef]
    [Google Scholar]
http://instance.metastore.ingenta.com/content/journal/jgv/10.1099/vir.0.2008/001461-0
Loading
/content/journal/jgv/10.1099/vir.0.2008/001461-0
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