Skip to main content
NCBI home page
The EMBO Journal logoLink to The EMBO Journal
. 1993 Dec 15;12(13):5105–5112. doi: 10.1002/j.1460-2075.1993.tb06205.x

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.

P Beaufils 1, D Choquet 1, R Z Mamoun 1, B Malissen 1
PMCID: PMC413772  PMID: 8262054

Abstract

The cytoplasmic domains of the transducing subunits associated with B and T cell antigen receptors contain a common amino acid motif consisting of two precisely spaced Tyr-X-X-Leu/Ile sequences (where X corresponds to a variable residue). Expression of a single copy of this motif suffices to initiate B or T cell activation. The bovine leukaemia virus (BLV) is a B cell lymphotropic retrovirus which causes a non-neoplasic proliferation of B cells. The cytoplasmic domain of the BLV transmembrane envelope glycoprotein, gp30, possesses two overlapping copies of the Tyr-X-X-Leu/Ile-containing motif which could participate in the induction of B cell activation. Similarly, the N-terminal cytoplasmic domain of the latent membrane protein 2A (LMP2A) of the Epstein-Barr virus (EBV) contains a single copy of the Tyr-X-X-Leu/Ile-containing motif which could play a critical role in B cell transformation. To determine whether these two virus-encoded cytoplasmic domains are endowed with signalling functions, we constructed chimeric proteins by replacing the cytoplasmic tail of CD8-alpha with that of either BLV gp30 or EBV LMP2A. We show here that, once separately expressed in B or T cell lines, these chimeras are capable of triggering both calcium responses and cytokine production when cross-linked with an antibody to CD8-alpha. Furthermore, using site-directed mutagenesis, we demonstrated unequivocally that this signalling function may be accounted for by the Tyr-X-X-Leu/Ile motifs they contain.(ABSTRACT TRUNCATED AT 250 WORDS)

Full text

PDF
5105

Images in this article

5107Image
on p.5107

Selected References

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

  1. Alber G., Kim K. M., Weiser P., Riesterer C., Carsetti R., Reth M. Molecular mimicry of the antigen receptor signalling motif by transmembrane proteins of the Epstein-Barr virus and the bovine leukaemia virus. Curr Biol. 1993 Jun 1;3(6):333–339. doi: 10.1016/0960-9822(93)90196-u. [DOI] [PubMed] [Google Scholar]
  2. Ben-David Y., Bernstein A. Friend virus-induced erythroleukemia and the multistage nature of cancer. Cell. 1991 Sep 6;66(5):831–834. doi: 10.1016/0092-8674(91)90428-2. [DOI] [PubMed] [Google Scholar]
  3. Blanc D., Bron C., Gabert J., Letourneur F., MacDonald H. R., Malissen B. Gene transfer of the Ly-3 chain gene of the mouse CD8 molecular complex: co-transfer with the Ly-2 polypeptide gene results in detectable cell surface expression of the Ly-3 antigenic determinants. Eur J Immunol. 1988 Apr;18(4):613–619. doi: 10.1002/eji.1830180419. [DOI] [PubMed] [Google Scholar]
  4. Bonnerot C., Amigorena S., Choquet D., Pavlovich R., Choukroun V., Fridman W. H. Role of associated gamma-chain in tyrosine kinase activation via murine Fc gamma RIII. EMBO J. 1992 Jul;11(7):2747–2757. doi: 10.1002/j.1460-2075.1992.tb05340.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Brody B. A., Rhee S. S., Sommerfelt M. A., Hunter E. A viral protease-mediated cleavage of the transmembrane glycoprotein of Mason-Pfizer monkey virus can be suppressed by mutations within the matrix protein. Proc Natl Acad Sci U S A. 1992 Apr 15;89(8):3443–3447. doi: 10.1073/pnas.89.8.3443. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Burdin N., Péronne C., Banchereau J., Rousset F. Epstein-Barr virus transformation induces B lymphocytes to produce human interleukin 10. J Exp Med. 1993 Feb 1;177(2):295–304. doi: 10.1084/jem.177.2.295. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Burkhardt A. L., Bolen J. B., Kieff E., Longnecker R. An Epstein-Barr virus transformation-associated membrane protein interacts with src family tyrosine kinases. J Virol. 1992 Aug;66(8):5161–5167. doi: 10.1128/jvi.66.8.5161-5167.1992. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Burny A., Cleuter Y., Kettmann R., Mammerickx M., Marbaix G., Portetelle D., Van den Broeke A., Willems L., Thomas R. Bovine leukaemia: facts and hypotheses derived from the study of an infectious cancer. Cancer Surv. 1987;6(1):139–159. [PubMed] [Google Scholar]
  9. Chan A. C., Iwashima M., Turck C. W., Weiss A. ZAP-70: a 70 kd protein-tyrosine kinase that associates with the TCR zeta chain. Cell. 1992 Nov 13;71(4):649–662. doi: 10.1016/0092-8674(92)90598-7. [DOI] [PubMed] [Google Scholar]
  10. Choquet D., Partiseti M., Amigorena S., Bonnerot C., Fridman W. H., Korn H. Cross-linking of IgG receptors inhibits membrane immunoglobulin-stimulated calcium influx in B lymphocytes. J Cell Biol. 1993 Apr;121(2):355–363. doi: 10.1083/jcb.121.2.355. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Clark M. R., Campbell K. S., Kazlauskas A., Johnson S. A., Hertz M., Potter T. A., Pleiman C., Cambier J. C. The B cell antigen receptor complex: association of Ig-alpha and Ig-beta with distinct cytoplasmic effectors. Science. 1992 Oct 2;258(5079):123–126. doi: 10.1126/science.1439759. [DOI] [PubMed] [Google Scholar]
  12. Coffin J. M. Superantigens and endogenous retroviruses: a confluence of puzzles. Science. 1992 Jan 24;255(5043):411–413. doi: 10.1126/science.1310360. [DOI] [PubMed] [Google Scholar]
  13. Cohen D. I., Tani Y., Tian H., Boone E., Samelson L. E., Lane H. C. Participation of tyrosine phosphorylation in the cytopathic effect of human immunodeficiency virus-1. Science. 1992 Apr 24;256(5056):542–545. doi: 10.1126/science.1570514. [DOI] [PubMed] [Google Scholar]
  14. Demotz S., Grey H. M., Sette A. The minimal number of class II MHC-antigen complexes needed for T cell activation. Science. 1990 Aug 31;249(4972):1028–1030. doi: 10.1126/science.2118680. [DOI] [PubMed] [Google Scholar]
  15. Felber B. K., Derse D., Athanassopoulos A., Campbell M., Pavlakis G. N. Cross-activation of the Rex proteins of HTLV-I and BLV and of the Rev protein of HIV-1 and nonreciprocal interactions with their RNA responsive elements. New Biol. 1989 Dec;1(3):318–328. [PubMed] [Google Scholar]
  16. Gooding L. R. Virus proteins that counteract host immune defenses. Cell. 1992 Oct 2;71(1):5–7. doi: 10.1016/0092-8674(92)90259-f. [DOI] [PubMed] [Google Scholar]
  17. Henderson S., Rowe M., Gregory C., Croom-Carter D., Wang F., Longnecker R., Kieff E., Rickinson A. Induction of bcl-2 expression by Epstein-Barr virus latent membrane protein 1 protects infected B cells from programmed cell death. Cell. 1991 Jun 28;65(7):1107–1115. doi: 10.1016/0092-8674(91)90007-l. [DOI] [PubMed] [Google Scholar]
  18. Hutchcroft J. E., Harrison M. L., Geahlen R. L. Association of the 72-kDa protein-tyrosine kinase PTK72 with the B cell antigen receptor. J Biol Chem. 1992 Apr 25;267(12):8613–8619. [PubMed] [Google Scholar]
  19. Irving B. A., Weiss A. The cytoplasmic domain of the T cell receptor zeta chain is sufficient to couple to receptor-associated signal transduction pathways. Cell. 1991 Mar 8;64(5):891–901. doi: 10.1016/0092-8674(91)90314-o. [DOI] [PubMed] [Google Scholar]
  20. Kim K. M., Alber G., Weiser P., Reth M. Differential signaling through the Ig-alpha and Ig-beta components of the B cell antigen receptor. Eur J Immunol. 1993 Apr;23(4):911–916. doi: 10.1002/eji.1830230422. [DOI] [PubMed] [Google Scholar]
  21. Laux G., Perricaudet M., Farrell P. J. A spliced Epstein-Barr virus gene expressed in immortalized lymphocytes is created by circularization of the linear viral genome. EMBO J. 1988 Mar;7(3):769–774. doi: 10.1002/j.1460-2075.1988.tb02874.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Leo O., Foo M., Sachs D. H., Samelson L. E., Bluestone J. A. Identification of a monoclonal antibody specific for a murine T3 polypeptide. Proc Natl Acad Sci U S A. 1987 Mar;84(5):1374–1378. doi: 10.1073/pnas.84.5.1374. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Letourneur F., Klausner R. D. A novel di-leucine motif and a tyrosine-based motif independently mediate lysosomal targeting and endocytosis of CD3 chains. Cell. 1992 Jun 26;69(7):1143–1157. doi: 10.1016/0092-8674(92)90636-q. [DOI] [PubMed] [Google Scholar]
  24. Letourneur F., Klausner R. D. Activation of T cells by a tyrosine kinase activation domain in the cytoplasmic tail of CD3 epsilon. Science. 1992 Jan 3;255(5040):79–82. doi: 10.1126/science.1532456. [DOI] [PubMed] [Google Scholar]
  25. Longnecker R., Kieff E. A second Epstein-Barr virus membrane protein (LMP2) is expressed in latent infection and colocalizes with LMP1. J Virol. 1990 May;64(5):2319–2326. doi: 10.1128/jvi.64.5.2319-2326.1990. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Longnecker R., Miller C. L., Miao X. Q., Marchini A., Kieff E. The only domain which distinguishes Epstein-Barr virus latent membrane protein 2A (LMP2A) from LMP2B is dispensable for lymphocyte infection and growth transformation in vitro; LMP2A is therefore nonessential. J Virol. 1992 Nov;66(11):6461–6469. doi: 10.1128/jvi.66.11.6461-6469.1992. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Mamoun R. Z., Morisson M., Rebeyrotte N., Busetta B., Couez D., Kettmann R., Hospital M., Guillemain B. Sequence variability of bovine leukemia virus env gene and its relevance to the structure and antigenicity of the glycoproteins. J Virol. 1990 Sep;64(9):4180–4188. doi: 10.1128/jvi.64.9.4180-4188.1990. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Miller C. L., Longnecker R., Kieff E. Epstein-Barr virus latent membrane protein 2A blocks calcium mobilization in B lymphocytes. J Virol. 1993 Jun;67(6):3087–3094. doi: 10.1128/jvi.67.6.3087-3094.1993. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. Necker A., Rebaï N., Matthes M., Jouvin-Marche E., Cazenave P. A., Swarnworawong P., Palmer E., MacDonald H. R., Malissen B. Monoclonal antibodies raised against engineered soluble mouse T cell receptors and specific for V alpha 8-, V beta 2- or V beta 10-bearing T cells. Eur J Immunol. 1991 Dec;21(12):3035–3040. doi: 10.1002/eji.1830211220. [DOI] [PubMed] [Google Scholar]
  30. Ozel M., Pauli G., Gelderblom H. R. The organization of the envelope projections on the surface of HIV. Arch Virol. 1988;100(3-4):255–266. doi: 10.1007/BF01487688. [DOI] [PubMed] [Google Scholar]
  31. Pierres A., Naquet P., Van Agthoven A., Bekkhoucha F., Denizot F., Mishal Z., Schmitt-Verhulst A. M., Pierres M. A rat anti-mouse T4 monoclonal antibody (H129.19) inhibits the proliferation of Ia-reactive T cell clones and delineates two phenotypically distinct (T4+, Lyt-2,3-, and T4-, Lyt-2,3+) subsets among anti-Ia cytolytic T cell clones. J Immunol. 1984 Jun;132(6):2775–2782. [PubMed] [Google Scholar]
  32. Qu L., Rowe D. T. Epstein-Barr virus latent gene expression in uncultured peripheral blood lymphocytes. J Virol. 1992 Jun;66(6):3715–3724. doi: 10.1128/jvi.66.6.3715-3724.1992. [DOI] [PMC free article] [PubMed] [Google Scholar]
  33. Reth M. Antigen receptor tail clue. Nature. 1989 Mar 30;338(6214):383–384. doi: 10.1038/338383b0. [DOI] [PubMed] [Google Scholar]
  34. Romeo C., Amiot M., Seed B. Sequence requirements for induction of cytolysis by the T cell antigen/Fc receptor zeta chain. Cell. 1992 Mar 6;68(5):889–897. doi: 10.1016/0092-8674(92)90032-8. [DOI] [PubMed] [Google Scholar]
  35. Sample J., Liebowitz D., Kieff E. Two related Epstein-Barr virus membrane proteins are encoded by separate genes. J Virol. 1989 Feb;63(2):933–937. doi: 10.1128/jvi.63.2.933-937.1989. [DOI] [PMC free article] [PubMed] [Google Scholar]
  36. Seiki M., Hattori S., Hirayama Y., Yoshida M. Human adult T-cell leukemia virus: complete nucleotide sequence of the provirus genome integrated in leukemia cell DNA. Proc Natl Acad Sci U S A. 1983 Jun;80(12):3618–3622. doi: 10.1073/pnas.80.12.3618. [DOI] [PMC free article] [PubMed] [Google Scholar]
  37. Songyang Z., Shoelson S. E., Chaudhuri M., Gish G., Pawson T., Haser W. G., King F., Roberts T., Ratnofsky S., Lechleider R. J. SH2 domains recognize specific phosphopeptide sequences. Cell. 1993 Mar 12;72(5):767–778. doi: 10.1016/0092-8674(93)90404-e. [DOI] [PubMed] [Google Scholar]
  38. Sonigo P., Barker C., Hunter E., Wain-Hobson S. Nucleotide sequence of Mason-Pfizer monkey virus: an immunosuppressive D-type retrovirus. Cell. 1986 May 9;45(3):375–385. doi: 10.1016/0092-8674(86)90323-5. [DOI] [PubMed] [Google Scholar]
  39. Takebe Y., Seiki M., Fujisawa J., Hoy P., Yokota K., Arai K., Yoshida M., Arai N. SR alpha promoter: an efficient and versatile mammalian cDNA expression system composed of the simian virus 40 early promoter and the R-U5 segment of human T-cell leukemia virus type 1 long terminal repeat. Mol Cell Biol. 1988 Jan;8(1):466–472. doi: 10.1128/mcb.8.1.466. [DOI] [PMC free article] [PubMed] [Google Scholar]
  40. Taniguchi T., Kobayashi T., Kondo J., Takahashi K., Nakamura H., Suzuki J., Nagai K., Yamada T., Nakamura S., Yamamura H. Molecular cloning of a porcine gene syk that encodes a 72-kDa protein-tyrosine kinase showing high susceptibility to proteolysis. J Biol Chem. 1991 Aug 25;266(24):15790–15796. [PubMed] [Google Scholar]
  41. Wange R. L., Kong A. N., Samelson L. E. A tyrosine-phosphorylated 70-kDa protein binds a photoaffinity analogue of ATP and associates with both the zeta chain and CD3 components of the activated T cell antigen receptor. J Biol Chem. 1992 Jun 15;267(17):11685–11688. [PubMed] [Google Scholar]
  42. Wegener A. M., Letourneur F., Hoeveler A., Brocker T., Luton F., Malissen B. The T cell receptor/CD3 complex is composed of at least two autonomous transduction modules. Cell. 1992 Jan 10;68(1):83–95. doi: 10.1016/0092-8674(92)90208-t. [DOI] [PubMed] [Google Scholar]
  43. White J., Blackman M., Bill J., Kappler J., Marrack P., Gold D. P., Born W. Two better cell lines for making hybridomas expressing specific T cell receptors. J Immunol. 1989 Sep 15;143(6):1822–1825. [PubMed] [Google Scholar]

Articles from The EMBO Journal are provided here courtesy of Nature Publishing Group

RESOURCES