Skip to main content
NCBI home page
The Journal of Experimental Medicine logoLink to The Journal of Experimental Medicine
. 1995 Jan 1;181(1):161–168. doi: 10.1084/jem.181.1.161

Molecular mechanisms that control expression of the B lymphocyte antigen receptor complex

PMCID: PMC2191827  PMID: 7807000

Abstract

The B cell receptor for antigen (BCR) is a complex of membrane immunoglobulin (mIg) and at least two other proteins, Ig alpha (mb-1) and Ig beta (B29). This complex promotes surface expression of the BCR and acts to transduce an activation signal. We have used a system of mu heavy chain constructs transfected into murine B cell lines to probe structure-function relationships in the BCR complex. One mutant mu chain, in which two polar transmembrane residues (Tyr587, Ser588) are replaced with valine, fails to associate with Ig alpha and Ig beta and is incapable of transducing signals as a result of mIg cross-linking. This mutant is expressed on the surface at high levels when transfected into a plasmacytoma line that lacks Ig alpha, whereas wild-type mu is retained in this cell line in the endoplasmic reticulum. Pulse-chase and immunoprecipitation analyses indicate that the mutant is more rapidly released from calnexin than the wild-type mu. Further, transfection of Ig alpha into this Ig alpha-negative cell line allows release of the mu chain from calnexin and surface expression of the BCR. These results identify the transmembrane residues of mu heavy chain that control binding to calnexin and Ig alpha, and suggest that calnexin-dependent intracellular retention is an important control mechanism for expression of the BCR complex.

Full Text

The Full Text of this article is available as a PDF (1.1 MB).

Selected References

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

  1. Ahluwalia N., Bergeron J. J., Wada I., Degen E., Williams D. B. The p88 molecular chaperone is identical to the endoplasmic reticulum membrane protein, calnexin. J Biol Chem. 1992 May 25;267(15):10914–10918. [PubMed] [Google Scholar]
  2. Campbell K. S., Hager E. J., Cambier J. C. Alpha-chains of IgM and IgD antigen receptor complexes are differentially N-glycosylated MB-1-related molecules. J Immunol. 1991 Sep 1;147(5):1575–1580. [PubMed] [Google Scholar]
  3. Costa T. E., Franke R. R., Sanchez M., Misulovin Z., Nussenzweig M. C. Functional reconstitution of an immunoglobulin antigen receptor in T cells. J Exp Med. 1992 Jun 1;175(6):1669–1676. doi: 10.1084/jem.175.6.1669. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Grupp S. A., Campbell K., Mitchell R. N., Cambier J. C., Abbas A. K. Signaling-defective mutants of the B lymphocyte antigen receptor fail to associate with Ig-alpha and Ig-beta/gamma. J Biol Chem. 1993 Dec 5;268(34):25776–25779. [PubMed] [Google Scholar]
  5. Hermanson G. G., Eisenberg D., Kincade P. W., Wall R. B29: a member of the immunoglobulin gene superfamily exclusively expressed on beta-lineage cells. Proc Natl Acad Sci U S A. 1988 Sep;85(18):6890–6894. doi: 10.1073/pnas.85.18.6890. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Hochstenbach F., David V., Watkins S., Brenner M. B. Endoplasmic reticulum resident protein of 90 kilodaltons associates with the T- and B-cell antigen receptors and major histocompatibility complex antigens during their assembly. Proc Natl Acad Sci U S A. 1992 May 15;89(10):4734–4738. doi: 10.1073/pnas.89.10.4734. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Hombach J., Leclercq L., Radbruch A., Rajewsky K., Reth M. A novel 34-kd protein co-isolated with the IgM molecule in surface IgM-expressing cells. EMBO J. 1988 Nov;7(11):3451–3456. doi: 10.1002/j.1460-2075.1988.tb03219.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Hombach J., Lottspeich F., Reth M. Identification of the genes encoding the IgM-alpha and Ig-beta components of the IgM antigen receptor complex by amino-terminal sequencing. Eur J Immunol. 1990 Dec;20(12):2795–2799. doi: 10.1002/eji.1830201239. [DOI] [PubMed] [Google Scholar]
  9. Hombach J., Sablitzky F., Rajewsky K., Reth M. Transfected plasmacytoma cells do not transport the membrane form of IgM to the cell surface. J Exp Med. 1988 Feb 1;167(2):652–657. doi: 10.1084/jem.167.2.652. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Hombach J., Tsubata T., Leclercq L., Stappert H., Reth M. Molecular components of the B-cell antigen receptor complex of the IgM class. Nature. 1990 Feb 22;343(6260):760–762. doi: 10.1038/343760a0. [DOI] [PubMed] [Google Scholar]
  11. Jackson M. R., Cohen-Doyle M. F., Peterson P. A., Williams D. B. Regulation of MHC class I transport by the molecular chaperone, calnexin (p88, IP90). Science. 1994 Jan 21;263(5145):384–387. doi: 10.1126/science.8278813. [DOI] [PubMed] [Google Scholar]
  12. Kashiwamura S., Koyama T., Matsuo T., Steinmetz M., Kimoto M., Sakaguchi N. Structure of the murine mb-1 gene encoding a putative sIgM-associated molecule. J Immunol. 1990 Jul 1;145(1):337–343. [PubMed] [Google Scholar]
  13. Klausner R. D., Lippincott-Schwartz J., Bonifacino J. S. The T cell antigen receptor: insights into organelle biology. Annu Rev Cell Biol. 1990;6:403–431. doi: 10.1146/annurev.cb.06.110190.002155. [DOI] [PubMed] [Google Scholar]
  14. Matsuuchi L., Gold M. R., Travis A., Grosschedl R., DeFranco A. L., Kelly R. B. The membrane IgM-associated proteins MB-1 and Ig-beta are sufficient to promote surface expression of a partially functional B-cell antigen receptor in a nonlymphoid cell line. Proc Natl Acad Sci U S A. 1992 Apr 15;89(8):3404–3408. doi: 10.1073/pnas.89.8.3404. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Mitchell R. N., Shaw A. C., Weaver Y. K., Leder P., Abbas A. K. Cytoplasmic tail deletion converts membrane immunoglobulin to a phosphatidylinositol-linked form lacking signaling and efficient antigen internalization functions. J Biol Chem. 1991 May 15;266(14):8856–8860. [PubMed] [Google Scholar]
  16. Ou W. J., Cameron P. H., Thomas D. Y., Bergeron J. J. Association of folding intermediates of glycoproteins with calnexin during protein maturation. Nature. 1993 Aug 26;364(6440):771–776. doi: 10.1038/364771a0. [DOI] [PubMed] [Google Scholar]
  17. Patel K. J., Neuberger M. S. Antigen presentation by the B cell antigen receptor is driven by the alpha/beta sheath and occurs independently of its cytoplasmic tyrosines. Cell. 1993 Sep 10;74(5):939–946. doi: 10.1016/0092-8674(93)90473-4. [DOI] [PubMed] [Google Scholar]
  18. Rajagopalan S., Xu Y., Brenner M. B. Retention of unassembled components of integral membrane proteins by calnexin. Science. 1994 Jan 21;263(5145):387–390. doi: 10.1126/science.8278814. [DOI] [PubMed] [Google Scholar]
  19. Reth M. Antigen receptors on B lymphocytes. Annu Rev Immunol. 1992;10:97–121. doi: 10.1146/annurev.iy.10.040192.000525. [DOI] [PubMed] [Google Scholar]
  20. Sakaguchi N., Kashiwamura S., Kimoto M., Thalmann P., Melchers F. B lymphocyte lineage-restricted expression of mb-1, a gene with CD3-like structural properties. EMBO J. 1988 Nov;7(11):3457–3464. doi: 10.1002/j.1460-2075.1988.tb03220.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Sanchez M., Misulovin Z., Burkhardt A. L., Mahajan S., Costa T., Franke R., Bolen J. B., Nussenzweig M. Signal transduction by immunoglobulin is mediated through Ig alpha and Ig beta. J Exp Med. 1993 Sep 1;178(3):1049–1055. doi: 10.1084/jem.178.3.1049. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Schreiber K. L., Bell M. P., Huntoon C. J., Rajagopalan S., Brenner M. B., McKean D. J. Class II histocompatibility molecules associate with calnexin during assembly in the endoplasmic reticulum. Int Immunol. 1994 Jan;6(1):101–111. doi: 10.1093/intimm/6.1.101. [DOI] [PubMed] [Google Scholar]
  23. Shaw A. C., Mitchell R. N., Weaver Y. K., Campos-Torres J., Abbas A. K., Leder P. Mutations of immunoglobulin transmembrane and cytoplasmic domains: effects on intracellular signaling and antigen presentation. Cell. 1990 Oct 19;63(2):381–392. doi: 10.1016/0092-8674(90)90171-a. [DOI] [PubMed] [Google Scholar]
  24. Sitia R., Neuberger M., Alberini C., Bet P., Fra A., Valetti C., Williams G., Milstein C. Developmental regulation of IgM secretion: the role of the carboxy-terminal cysteine. Cell. 1990 Mar 9;60(5):781–790. doi: 10.1016/0092-8674(90)90092-s. [DOI] [PubMed] [Google Scholar]
  25. Stevens T. L., Blum J. H., Foy S. P., Matsuuchi L., DeFranco A. L. A mutation of the mu transmembrane that disrupts endoplasmic reticulum retention. Effects on association with accessory proteins and signal transduction. J Immunol. 1994 May 1;152(9):4397–4406. [PubMed] [Google Scholar]
  26. Van Noesel C. J., Borst J., De Vries E. F., Van Lier R. A. Identification of two distinct phosphoproteins as components of the human B cell antigen receptor complex. Eur J Immunol. 1990 Dec;20(12):2789–2793. doi: 10.1002/eji.1830201238. [DOI] [PubMed] [Google Scholar]
  27. Van Noesel C. J., Brouns G. S., van Schijndel G. M., Bende R. J., Mason D. Y., Borst J., van Lier R. A. Comparison of human B cell antigen receptor complexes: membrane-expressed forms of immunoglobulin (Ig)M, IgD, and IgG are associated with structurally related heterodimers. J Exp Med. 1992 Jun 1;175(6):1511–1519. doi: 10.1084/jem.175.6.1511. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Williams G. T., Venkitaraman A. R., Gilmore D. J., Neuberger M. S. The sequence of the mu transmembrane segment determines the tissue specificity of the transport of immunoglobulin M to the cell surface. J Exp Med. 1990 Mar 1;171(3):947–952. doi: 10.1084/jem.171.3.947. [DOI] [PMC free article] [PubMed] [Google Scholar]

Articles from The Journal of Experimental Medicine are provided here courtesy of The Rockefeller University Press

RESOURCES