Assembled Pre-B Cell Receptor Complexes Are Retained in the Endoplasmic Reticulum by a Mechanism That Is Not Selective for the Pseudo-light Chain*

The pre-B cell receptor (BCR) complex, consisting of μ heavy chain, a pseudo-light chain, and the Mb-1/B29 heterodimer, directs the transition to the mature B cell stage. Plasma membrane expression of the pre-BCR is extremely low, despite its presumed signaling function. We have compared assembly and intracellular transport of the pre-BCR complex with that of the BCR complex in mature B cells. Synthesis and assembly rate of pre-BCR and BCR components are comparable. However, the pre-BCR is subject to a highly efficient retention mechanism, which only allows exit of a few percent of the complexes from the endoplasmic reticulum (ER). This small transported pool of pre-BCR complexes is significantly enriched for protein-tyrosine kinase activity, as compared with the ER-localized receptor pool. Accordingly, the Src-related tyrosine kinase Lyn was found in the transported glycoprotein fraction but not in association with ER-localized glycoproteins. Upon introduction of a conventional light chain into pre-B cells, plasma membrane receptor levels increased, but the efficiency of intracellular transport of the receptor complex was not restored to that in mature B cells. This indicates that the ER retention mechanism is not selective for the pseudo-light chain and may be inherent to pre-B cells. We propose that this retention mechanism contributes to the regulation of pre-BCR-mediated signal transduction.

[1]  J. Salamero,et al.  Internalization of B cell and pre‐B cell receptors is regulated by tyrosine kinase and phosphatase activities , 1995, European journal of immunology.

[2]  E. Jaffe,et al.  CD79a: a novel marker for B-cell neoplasms in routinely processed tissue samples. , 1995, Blood.

[3]  M. Nussenzweig,et al.  The role of Ig beta in precursor B cell transition and allelic exclusion. , 1995, Science.

[4]  J. Borst,et al.  Assembly and intracellular transport of the human B cell antigen receptor complex. , 1995, International immunology.

[5]  C. Saint‐Ruf,et al.  Analysis and expression of a cloned pre-T cell receptor gene. , 1994, Science.

[6]  A. Berns,et al.  CD3 components at the surface of pro‐T cells can mediate pre‐T cell development in vivo , 1994, European journal of immunology.

[7]  D. Blaise,et al.  Discrete early pro‐B and pre‐B stages in normal human bone marrow as defined by surface pseudo‐light chain expression , 1994, European journal of immunology.

[8]  D. Mason,et al.  The structure of the μ/pseudo light chain complex on human pre‐B cells is consistent with a function in signal transduction , 1993, European journal of immunology.

[9]  D. Olive,et al.  Structure, biosynthesis, and transduction properties of the human mu-psi L complex: similar behavior of preB and intermediate preB-B cells in transducing ability. , 1993, International immunology.

[10]  M. Cooper,et al.  Expression of surrogate light chain receptors is restricted to a late stage in pre-B cell differentiation , 1993, Cell.

[11]  D. Mason,et al.  Antigen Receptors on T and B Lymphocytes: Parallels in Organization and Function , 1993, Immunological reviews.

[12]  K. Rajewsky,et al.  Immunoglobulin heavy and light chain genes rearrange independently at early stages of B cell development , 1993, Cell.

[13]  J. Haimovich,et al.  Polymerization of secretory IgM in B lymphocytes is prevented by a prior targeting to a degradation pathway. , 1992, The Journal of biological chemistry.

[14]  J. Cambier,et al.  Human pre-B and B cell membrane mu-chains are noncovalently associated with a disulfide-linked complex containing a product of the B29 gene. , 1992, Journal of immunology.

[15]  M. Cooper,et al.  Heterogeneity of immunoglobulin-associated molecules on human B cells identified by monoclonal antibodies. , 1992, Proceedings of the National Academy of Sciences of the United States of America.

[16]  E. Clark,et al.  Characterization of molecular components associated with surface immunoglobulin M in human B lymphocytes: Presence of tyrosine and serine/threonine protein kinases , 1992, European journal of immunology.

[17]  K. Rajewsky,et al.  A critical role of λ5 protein in B cell development , 1992, Cell.

[18]  K. Rajewsky,et al.  Targeted disruption of µ chain membrane exon causes loss of heavy-chain allelic exclusion , 1992, Nature.

[19]  J. V. van Dongen,et al.  The IgM-associated protein mb-1 as a marker of normal and neoplastic B cells. , 1991, Journal of immunology.

[20]  M. Cooper,et al.  Normal pre-B cells express a receptor complex of mu heavy chains and surrogate light-chain proteins. , 1991, Proceedings of the National Academy of Sciences of the United States of America.

[21]  Klaus Rajewsky,et al.  A B cell-deficient mouse by targeted disruption of the membrane exon of the immunoglobulin μ chain gene , 1991, Nature.

[22]  M. Kimoto,et al.  Signal transmission through the B cell-specific MB-1 molecule at the pre-B cell stage. , 1991, International immunology.

[23]  T. Yamamoto,et al.  Association of B cell antigen receptor with protein tyrosine kinase Lyn. , 1991, Science.

[24]  S. Pillai,et al.  The omega/lambda 5 surrogate immunoglobulin light chain is expressed on the surface of transitional B lymphocytes in murine bone marrow , 1991, The Journal of experimental medicine.

[25]  H. Karasuyama,et al.  The proteins encoded by the VpreB and lambda 5 pre-B cell-specific genes can associate with each other and with mu heavy chain , 1990, The Journal of experimental medicine.

[26]  M. Reth,et al.  The products of pre-B cell-specific genes (lambda 5 and VpreB) and the immunoglobulin mu chain form a complex that is transported onto the cell surface , 1990, The Journal of experimental medicine.

[27]  K. Shigemoto,et al.  Two types of mu chain complexes are expressed during differentiation from pre‐B to mature B cells. , 1990, The EMBO journal.

[28]  C. Alberini,et al.  Developmental regulation of IgM secretion: The role of the carboxy-terminal cysteine , 1990, Cell.

[29]  M. Neuberger,et al.  The sequence of the mu transmembrane segment determines the tissue specificity of the transport of immunoglobulin M to the cell surface , 1990, The Journal of experimental medicine.

[30]  L. Hendershot,et al.  Mu heavy chains can associate with a pseudo-light chain complex (psi L) in human pre-B cell lines. , 1989, International immunology.

[31]  J. Kearney,et al.  Assembly and secretion of heavy chains that do not associate posttranslationally with immunoglobulin heavy chain-binding protein , 1987, The Journal of cell biology.

[32]  M. Reth.  Antigen receptors on B lymphocytes. , 1992, Annual review of immunology.

[33]  S. Kornfeld,et al.  Comparative aspects of glycoprotein structure. , 1976, Annual review of biochemistry.