Latent membrane protein 1 of Epstein-Barr virus interacts with JAK3 and activates STAT proteins (original) (raw)

Abstract

Latent membrane protein 1 (LMP1) acts like a permanently activated receptor of the tumor necrosis factor (TNF)-receptor superfamily and is absolutely required for B cell immortalization by Epstein-Barr virus. Molecular and biochemical approaches demonstrated that LMP1 usurps cellular signaling pathways resulting in the induction of NF-kappaB and AP-1 via two C-terminal activating regions. We demonstrate here that a third region encompassing a proline rich sequence within the 33 bp repetitive stretch of LMP1's C-terminus is required for the activation of Janus kinase 3 (JAK3). The interaction of LMP1 and JAK3 leads to the enhanced tyrosine auto/transphosphorylation of JAK3 within minutes after crosslinking of a conditional NGF-R:LMP1 chimera and is a prerequisite for the activation of STAT transcription factors. These results reveal a novel activating region in the LMP1 C-terminus and identify the JAK/STAT pathway as a target of this viral integral membrane protein in B cells.

Full Text

The Full Text of this article is available as a PDF (280.1 KB).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Baichwal V. R., Sugden B. Transformation of Balb 3T3 cells by the BNLF-1 gene of Epstein-Barr virus. Oncogene. 1988 May;2(5):461–467. [PubMed] [Google Scholar]
  2. Briscoe J., Kohlhuber F., Müller M. JAKs and STATs branch out. Trends Cell Biol. 1996 Sep;6(9):336–340. doi: 10.1016/0962-8924(96)10028-3. [DOI] [PubMed] [Google Scholar]
  3. Catlett-Falcone R., Landowski T. H., Oshiro M. M., Turkson J., Levitzki A., Savino R., Ciliberto G., Moscinski L., Fernández-Luna J. L., Nuñez G. Constitutive activation of Stat3 signaling confers resistance to apoptosis in human U266 myeloma cells. Immunity. 1999 Jan;10(1):105–115. doi: 10.1016/s1074-7613(00)80011-4. [DOI] [PubMed] [Google Scholar]
  4. Cohen J. I., Wang F., Kieff E. Epstein-Barr virus nuclear protein 2 mutations define essential domains for transformation and transactivation. J Virol. 1991 May;65(5):2545–2554. doi: 10.1128/jvi.65.5.2545-2554.1991. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Darnell J. E., Jr STATs and gene regulation. Science. 1997 Sep 12;277(5332):1630–1635. doi: 10.1126/science.277.5332.1630. [DOI] [PubMed] [Google Scholar]
  6. Delecluse H. J., Hilsendegen T., Pich D., Zeidler R., Hammerschmidt W. Propagation and recovery of intact, infectious Epstein-Barr virus from prokaryotic to human cells. Proc Natl Acad Sci U S A. 1998 Jul 7;95(14):8245–8250. doi: 10.1073/pnas.95.14.8245. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Devergne O., Hatzivassiliou E., Izumi K. M., Kaye K. M., Kleijnen M. F., Kieff E., Mosialos G. Association of TRAF1, TRAF2, and TRAF3 with an Epstein-Barr virus LMP1 domain important for B-lymphocyte transformation: role in NF-kappaB activation. Mol Cell Biol. 1996 Dec;16(12):7098–7108. doi: 10.1128/mcb.16.12.7098. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Eliopoulos A. G., Rickinson A. B. Epstein-Barr virus: LMP1 masquerades as an active receptor. Curr Biol. 1998 Mar 12;8(6):R196–R198. doi: 10.1016/s0960-9822(98)70123-x. [DOI] [PubMed] [Google Scholar]
  9. Eliopoulos A. G., Stack M., Dawson C. W., Kaye K. M., Hodgkin L., Sihota S., Rowe M., Young L. S. Epstein-Barr virus-encoded LMP1 and CD40 mediate IL-6 production in epithelial cells via an NF-kappaB pathway involving TNF receptor-associated factors. Oncogene. 1997 Jun 19;14(24):2899–2916. doi: 10.1038/sj.onc.1201258. [DOI] [PubMed] [Google Scholar]
  10. Eliopoulos A. G., Young L. S. Activation of the cJun N-terminal kinase (JNK) pathway by the Epstein-Barr virus-encoded latent membrane protein 1 (LMP1). Oncogene. 1998 Apr 2;16(13):1731–1742. doi: 10.1038/sj.onc.1201694. [DOI] [PubMed] [Google Scholar]
  11. Farrell P. J. Epstein-Barr virus immortalizing genes. Trends Microbiol. 1995 Mar;3(3):105–109. doi: 10.1016/s0966-842x(00)88891-5. [DOI] [PubMed] [Google Scholar]
  12. Floettmann J. E., Rowe M. Epstein-Barr virus latent membrane protein-1 (LMP1) C-terminus activation region 2 (CTAR2) maps to the far C-terminus and requires oligomerisation for NF-kappaB activation. Oncogene. 1997 Oct 9;15(15):1851–1858. doi: 10.1038/sj.onc.1201359. [DOI] [PubMed] [Google Scholar]
  13. Galibert L., Burdin N., de Saint-Vis B., Garrone P., Van Kooten C., Banchereau J., Rousset F. CD40 and B cell antigen receptor dual triggering of resting B lymphocytes turns on a partial germinal center phenotype. J Exp Med. 1996 Jan 1;183(1):77–85. doi: 10.1084/jem.183.1.77. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Gires O., Zimber-Strobl U., Gonnella R., Ueffing M., Marschall G., Zeidler R., Pich D., Hammerschmidt W. Latent membrane protein 1 of Epstein-Barr virus mimics a constitutively active receptor molecule. EMBO J. 1997 Oct 15;16(20):6131–6140. doi: 10.1093/emboj/16.20.6131. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Graham F. L., Smiley J., Russell W. C., Nairn R. Characteristics of a human cell line transformed by DNA from human adenovirus type 5. J Gen Virol. 1977 Jul;36(1):59–74. doi: 10.1099/0022-1317-36-1-59. [DOI] [PubMed] [Google Scholar]
  16. Hammarskjöld M. L., Simurda M. C. Epstein-Barr virus latent membrane protein transactivates the human immunodeficiency virus type 1 long terminal repeat through induction of NF-kappa B activity. J Virol. 1992 Nov;66(11):6496–6501. doi: 10.1128/jvi.66.11.6496-6501.1992. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Hammerschmidt W., Sugden B. Genetic analysis of immortalizing functions of Epstein-Barr virus in human B lymphocytes. Nature. 1989 Aug 3;340(6232):393–397. doi: 10.1038/340393a0. [DOI] [PubMed] [Google Scholar]
  18. Hanissian S. H., Geha R. S. Jak3 is associated with CD40 and is critical for CD40 induction of gene expression in B cells. Immunity. 1997 Apr;6(4):379–387. doi: 10.1016/s1074-7613(00)80281-2. [DOI] [PubMed] [Google Scholar]
  19. Hatzivassiliou E., Miller W. E., Raab-Traub N., Kieff E., Mosialos G. A fusion of the EBV latent membrane protein-1 (LMP1) transmembrane domains to the CD40 cytoplasmic domain is similar to LMP1 in constitutive activation of epidermal growth factor receptor expression, nuclear factor-kappa B, and stress-activated protein kinase. J Immunol. 1998 Feb 1;160(3):1116–1121. [PubMed] [Google Scholar]
  20. Huen D. S., Henderson S. A., Croom-Carter D., Rowe M. The Epstein-Barr virus latent membrane protein-1 (LMP1) mediates activation of NF-kappa B and cell surface phenotype via two effector regions in its carboxy-terminal cytoplasmic domain. Oncogene. 1995 Feb 2;10(3):549–560. [PubMed] [Google Scholar]
  21. Ihle J. N., Witthuhn B. A., Quelle F. W., Yamamoto K., Silvennoinen O. Signaling through the hematopoietic cytokine receptors. Annu Rev Immunol. 1995;13:369–398. doi: 10.1146/annurev.iy.13.040195.002101. [DOI] [PubMed] [Google Scholar]
  22. Ivashkiv L. B. Cytokines and STATs: how can signals achieve specificity? Immunity. 1995 Jul;3(1):1–4. doi: 10.1016/1074-7613(95)90152-3. [DOI] [PubMed] [Google Scholar]
  23. Izumi K. M., Kaye K. M., Kieff E. D. 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 A. 1997 Feb 18;94(4):1447–1452. doi: 10.1073/pnas.94.4.1447. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Izumi K. M., Kieff E. D. The Epstein-Barr virus oncogene product latent membrane protein 1 engages the tumor necrosis factor receptor-associated death domain protein to mediate B lymphocyte growth transformation and activate NF-kappaB. Proc Natl Acad Sci U S A. 1997 Nov 11;94(23):12592–12597. doi: 10.1073/pnas.94.23.12592. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Karras J. G., Wang Z., Huo L., Frank D. A., Rothstein T. L. Induction of STAT protein signaling through the CD40 receptor in B lymphocytes: distinct STAT activation following surface Ig and CD40 receptor engagement. J Immunol. 1997 Nov 1;159(9):4350–4355. [PubMed] [Google Scholar]
  26. Kawahara A., Minami Y., Miyazaki T., Ihle J. N., Taniguchi T. Critical role of the interleukin 2 (IL-2) receptor gamma-chain-associated Jak3 in the IL-2-induced c-fos and c-myc, but not bcl-2, gene induction. Proc Natl Acad Sci U S A. 1995 Sep 12;92(19):8724–8728. doi: 10.1073/pnas.92.19.8724. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Kaye K. M., Izumi K. M., Kieff E. Epstein-Barr virus latent membrane protein 1 is essential for B-lymphocyte growth transformation. Proc Natl Acad Sci U S A. 1993 Oct 1;90(19):9150–9154. doi: 10.1073/pnas.90.19.9150. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Kaye K. M., Izumi K. M., Mosialos G., Kieff E. The Epstein-Barr virus LMP1 cytoplasmic carboxy terminus is essential for B-lymphocyte transformation; fibroblast cocultivation complements a critical function within the terminal 155 residues. J Virol. 1995 Feb;69(2):675–683. doi: 10.1128/jvi.69.2.675-683.1995. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. Kieser A., Kaiser C., Hammerschmidt W. LMP1 signal transduction differs substantially from TNF receptor 1 signaling in the molecular functions of TRADD and TRAF2. EMBO J. 1999 May 4;18(9):2511–2521. doi: 10.1093/emboj/18.9.2511. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Kieser A., Kilger E., Gires O., Ueffing M., Kolch W., Hammerschmidt W. Epstein-Barr virus latent membrane protein-1 triggers AP-1 activity via the c-Jun N-terminal kinase cascade. EMBO J. 1997 Nov 3;16(21):6478–6485. doi: 10.1093/emboj/16.21.6478. [DOI] [PMC free article] [PubMed] [Google Scholar]
  31. Kilger E., Kieser A., Baumann M., Hammerschmidt W. Epstein-Barr virus-mediated B-cell proliferation is dependent upon latent membrane protein 1, which simulates an activated CD40 receptor. EMBO J. 1998 Mar 16;17(6):1700–1709. doi: 10.1093/emboj/17.6.1700. [DOI] [PMC free article] [PubMed] [Google Scholar]
  32. Laherty C. D., Hu H. M., Opipari A. W., Wang F., Dixit V. M. The Epstein-Barr virus LMP1 gene product induces A20 zinc finger protein expression by activating nuclear factor kappa B. J Biol Chem. 1992 Dec 5;267(34):24157–24160. [PubMed] [Google Scholar]
  33. Leonard W. J., O'Shea J. J. Jaks and STATs: biological implications. Annu Rev Immunol. 1998;16:293–322. doi: 10.1146/annurev.immunol.16.1.293. [DOI] [PubMed] [Google Scholar]
  34. Liebowitz D., Wang D., Kieff E. Orientation and patching of the latent infection membrane protein encoded by Epstein-Barr virus. J Virol. 1986 Apr;58(1):233–237. doi: 10.1128/jvi.58.1.233-237.1986. [DOI] [PMC free article] [PubMed] [Google Scholar]
  35. Macchi P., Villa A., Giliani S., Sacco M. G., Frattini A., Porta F., Ugazio A. G., Johnston J. A., Candotti F., O'Shea J. J. Mutations of Jak-3 gene in patients with autosomal severe combined immune deficiency (SCID). Nature. 1995 Sep 7;377(6544):65–68. doi: 10.1038/377065a0. [DOI] [PubMed] [Google Scholar]
  36. Miller W. E., Mosialos G., Kieff E., Raab-Traub N. Epstein-Barr virus LMP1 induction of the epidermal growth factor receptor is mediated through a TRAF signaling pathway distinct from NF-kappaB activation. J Virol. 1997 Jan;71(1):586–594. doi: 10.1128/jvi.71.1.586-594.1997. [DOI] [PMC free article] [PubMed] [Google Scholar]
  37. Mitchell T., Sugden B. Stimulation of NF-kappa B-mediated transcription by mutant derivatives of the latent membrane protein of Epstein-Barr virus. J Virol. 1995 May;69(5):2968–2976. doi: 10.1128/jvi.69.5.2968-2976.1995. [DOI] [PMC free article] [PubMed] [Google Scholar]
  38. Moorthy R. K., Thorley-Lawson D. A. All three domains of the Epstein-Barr virus-encoded latent membrane protein LMP-1 are required for transformation of rat-1 fibroblasts. J Virol. 1993 Mar;67(3):1638–1646. doi: 10.1128/jvi.67.3.1638-1646.1993. [DOI] [PMC free article] [PubMed] [Google Scholar]
  39. Mosialos G., Birkenbach M., Yalamanchili R., VanArsdale T., Ware C., Kieff E. The Epstein-Barr virus transforming protein LMP1 engages signaling proteins for the tumor necrosis factor receptor family. Cell. 1995 Feb 10;80(3):389–399. doi: 10.1016/0092-8674(95)90489-1. [DOI] [PubMed] [Google Scholar]
  40. Murakami M., Narazaki M., Hibi M., Yawata H., Yasukawa K., Hamaguchi M., Taga T., Kishimoto T. Critical cytoplasmic region of the interleukin 6 signal transducer gp130 is conserved in the cytokine receptor family. Proc Natl Acad Sci U S A. 1991 Dec 15;88(24):11349–11353. doi: 10.1073/pnas.88.24.11349. [DOI] [PMC free article] [PubMed] [Google Scholar]
  41. Murata T., Puri R. K. Comparison of IL-13- and IL-4-induced signaling in EBV-immortalized human B cells. Cell Immunol. 1997 Jan 10;175(1):33–40. doi: 10.1006/cimm.1996.1051. [DOI] [PubMed] [Google Scholar]
  42. Rodriguez-Tarduchy G., Collins M., López-Rivas A. Regulation of apoptosis in interleukin-3-dependent hemopoietic cells by interleukin-3 and calcium ionophores. EMBO J. 1990 Sep;9(9):2997–3002. doi: 10.1002/j.1460-2075.1990.tb07492.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  43. Russell S. M., Tayebi N., Nakajima H., Riedy M. C., Roberts J. L., Aman M. J., Migone T. S., Noguchi M., Markert M. L., Buckley R. H. Mutation of Jak3 in a patient with SCID: essential role of Jak3 in lymphoid development. Science. 1995 Nov 3;270(5237):797–800. doi: 10.1126/science.270.5237.797. [DOI] [PubMed] [Google Scholar]
  44. Sadowski H. B., Shuai K., Darnell J. E., Jr, Gilman M. Z. A common nuclear signal transduction pathway activated by growth factor and cytokine receptors. Science. 1993 Sep 24;261(5129):1739–1744. doi: 10.1126/science.8397445. [DOI] [PubMed] [Google Scholar]
  45. Sandberg M., Hammerschmidt W., Sugden B. Characterization of LMP-1's association with TRAF1, TRAF2, and TRAF3. J Virol. 1997 Jun;71(6):4649–4656. doi: 10.1128/jvi.71.6.4649-4656.1997. [DOI] [PMC free article] [PubMed] [Google Scholar]
  46. Schindler C., Shuai K., Prezioso V. R., Darnell J. E., Jr Interferon-dependent tyrosine phosphorylation of a latent cytoplasmic transcription factor. Science. 1992 Aug 7;257(5071):809–813. doi: 10.1126/science.1496401. [DOI] [PubMed] [Google Scholar]
  47. Silvennoinen O., Ihle J. N., Schlessinger J., Levy D. E. Interferon-induced nuclear signalling by Jak protein tyrosine kinases. Nature. 1993 Dec 9;366(6455):583–585. doi: 10.1038/366583a0. [DOI] [PubMed] [Google Scholar]
  48. Tomkinson B., Robertson E., Kieff E. Epstein-Barr virus nuclear proteins EBNA-3A and EBNA-3C are essential for B-lymphocyte growth transformation. J Virol. 1993 Apr;67(4):2014–2025. doi: 10.1128/jvi.67.4.2014-2025.1993. [DOI] [PMC free article] [PubMed] [Google Scholar]
  49. Tortolani P. J., Lal B. K., Riva A., Johnston J. A., Chen Y. Q., Reaman G. H., Beckwith M., Longo D., Ortaldo J. R., Bhatia K. Regulation of JAK3 expression and activation in human B cells and B cell malignancies. J Immunol. 1995 Dec 1;155(11):5220–5226. [PubMed] [Google Scholar]
  50. Tosato G., Tanner J., Jones K. D., Revel M., Pike S. E. Identification of interleukin-6 as an autocrine growth factor for Epstein-Barr virus-immortalized B cells. J Virol. 1990 Jun;64(6):3033–3041. doi: 10.1128/jvi.64.6.3033-3041.1990. [DOI] [PMC free article] [PubMed] [Google Scholar]
  51. Wang D., Liebowitz D., Kieff E. An EBV membrane protein expressed in immortalized lymphocytes transforms established rodent cells. Cell. 1985 Dec;43(3 Pt 2):831–840. doi: 10.1016/0092-8674(85)90256-9. [DOI] [PubMed] [Google Scholar]
  52. Wang F., Gregory C., Sample C., Rowe M., Liebowitz D., Murray R., Rickinson A., Kieff E. Epstein-Barr virus latent membrane protein (LMP1) and nuclear proteins 2 and 3C are effectors of phenotypic changes in B lymphocytes: EBNA-2 and LMP1 cooperatively induce CD23. J Virol. 1990 May;64(5):2309–2318. doi: 10.1128/jvi.64.5.2309-2318.1990. [DOI] [PMC free article] [PubMed] [Google Scholar]
  53. Weber-Nordt R. M., Egen C., Wehinger J., Ludwig W., Gouilleux-Gruart V., Mertelsmann R., Finke J. Constitutive activation of STAT proteins in primary lymphoid and myeloid leukemia cells and in Epstein-Barr virus (EBV)-related lymphoma cell lines. Blood. 1996 Aug 1;88(3):809–816. [PubMed] [Google Scholar]
  54. Witthuhn B. A., Silvennoinen O., Miura O., Lai K. S., Cwik C., Liu E. T., Ihle J. N. Involvement of the Jak-3 Janus kinase in signalling by interleukins 2 and 4 in lymphoid and myeloid cells. Nature. 1994 Jul 14;370(6485):153–157. doi: 10.1038/370153a0. [DOI] [PubMed] [Google Scholar]
  55. Xu X., Kang S. H., Heidenreich O., Okerholm M., O'Shea J. J., Nerenberg M. I. Constitutive activation of different Jak tyrosine kinases in human T cell leukemia virus type 1 (HTLV-1) tax protein or virus-transformed cells. J Clin Invest. 1995 Sep;96(3):1548–1555. doi: 10.1172/JCI118193. [DOI] [PMC free article] [PubMed] [Google Scholar]
  56. Yates J. L., Warren N., Sugden B. Stable replication of plasmids derived from Epstein-Barr virus in various mammalian cells. 1985 Feb 28-Mar 6Nature. 313(6005):812–815. doi: 10.1038/313812a0. [DOI] [PubMed] [Google Scholar]
  57. Zimber-Strobl U., Kempkes B., Marschall G., Zeidler R., Van Kooten C., Banchereau J., Bornkamm G. W., Hammerschmidt W. 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. 1996 Dec 16;15(24):7070–7078. [PMC free article] [PubMed] [Google Scholar]