Independent Trafficking of Ig-α/Ig-β and μ-Heavy Chain Is Facilitated by Dissociation of the B Cell Antigen Receptor Complex

Kim, Jin Hyang; Cramer, Lorraine A.; Mueller, Heather; Wilson, Bridget S.; Vilen, Barbara J.

doi:10.4049/jimmunol.175.1.147

Cited by 29 publications

(26 citation statements)

References 39 publications

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“…BCR engagement also destabilizes the sIg-Ig␣/␤ complex; physical separation of the antigen-binding and signaling components of the BCR is thought to act as a mechanism for receptor desensitization in anergic B cells (35,36), as well as to facilitate clathrin-mediated internalization of the receptor (37,38). Most sIg-dissociated Ig␣/␤ heterodimers remain on the cell surface (39,40); however, our preliminary investigation indicated that Ig␣/␤ did not remain in association with CD20.…”

Section: Discussionmentioning

confidence: 60%

CD20 Homo-oligomers Physically Associate with the B Cell Antigen Receptor

Polyak¹,

Li²,

Shariat

et al. 2008

Journal of Biological Chemistry

114

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B cell antigen receptor (BCR) signaling initiates sustained cellular calcium influx necessary for the development, differentiation, and activation of B lymphocytes. CD20 is a B cell-restricted tetraspanning protein organized in the plasma membrane as multimeric molecular complexes involved in BCR-activated calcium entry. Using coprecipitation of native CD20 with tagged or truncated forms of the molecule, we provide here direct evidence of CD20 homo-oligomerization into tetramers. Additionally, the function of CD20 was explored by examining its association with surface-labeled and intracellular proteins before and after BCR signaling. Two major surface-labeled proteins that coprecipitated with CD20 were identified as the heavy and light chains of cell surface IgM, the antigen-binding components of the BCR. After activation, BCR-CD20 complexes dissociated, and phosphoproteins and calmodulin-binding proteins were transiently recruited to CD20. These data provide new evidence of the involvement of CD20 in signaling downstream of the BCR and, together with the previously described involvement of CD20 in calcium influx, the first evidence of physical coupling of the BCR to a calcium entry pathway.Signaling from the BCR, 4 which is composed of antigenbinding immunoglobulin (Ig) and signaling Ig␣/Ig␤ subunits, is necessary for the development, differentiation, and activation of B lymphocytes. Tyrosine kinase-dependent activation of phospholipase C-␥2, one of many intracellular signaling events that follow BCR ligation, leads to rapid release of calcium from the lumen of the endoplasmic reticulum into the cytoplasm. Depletion of the intracellular calcium stores triggers a second phase of calcium mobilization, characterized by sustained calcium entry into the cell via plasma membrane-associated "store-operated" calcium entry (SOCE) channels (1, 2). The amplitude and duration of the calcium response is translated into differential gene expression by calcium-sensitive proteins, determining the cellular response to receptor engagement (3-5).Key molecular components of SOCE have recently been identified with the discovery and characterization of the endoplasmic reticulum calcium sensor, STIM1, and the pore-forming subunit of the Icrac channel, Orai1 (2, 4, 6). A point mutation in Orai1 causes a form of hereditary severe combined immune deficiency syndrome, emphasizing the importance of intracellular calcium in lymphocyte physiology. However, although SOCE is absent in T lymphocytes from these patients, SOCE in B lymphocytes is reduced but not abolished, indicating additional SOCE pathways in the B cell lineage (1, 7).Increasing evidence has indicated that CD20, a B cell-restricted member of the MS4A (multispanning 4A) family of tetraspanins, functions in calcium entry. Intracellular calcium levels were increased in non-B cells ectopically expressing CD20 by transfection, and a calcium-mediated current, similar to that observed in B cells, was detected by whole cell patch clamp analysis (8, 9). BCR-activated calcium entry was ...

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Section: Discussionmentioning

confidence: 60%

CD20 Homo-oligomers Physically Associate with the B Cell Antigen Receptor

Polyak¹,

Li²,

Shariat

et al. 2008

Journal of Biological Chemistry

114

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“…Typically, 5-l samples of complexes between nucleosomes and the different laminins (20)(21)(22)(23)(24)(25)(26)(27)(28)(29)(30) Analysis of proteins applied to PVDF membranes. Nucleosomes were radiolabeled with 125 I using Iodo-Beads iodination reagent (Pierce).…”

Section: Methodsmentioning

confidence: 99%

“…Samples were finally stained with uranyl acetate and lead citrate before examination by electron microscopy and evaluation as described above. In all experiments, molecules were deemed to be colocalized when 80-90% of the different sized goldconjugated antibodies met the 30 nm proximity criterion (20,21).…”

Section: Nucleosome Binding Of Aberrant Laminin ␤1 In Lupus Nephritismentioning

confidence: 99%

Pathogenic Mechanisms in Lupus Nephritis: Nucleosomes Bind Aberrant Laminin β1 With High Affinity and Colocalize in the Electron‐Dense Deposits

Olin

Mörgelin

Truedsson

et al. 2014

Arthritis & Rheumatology

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Objective. Apoptotic nucleosomes are structurally and immunologically involved in lupus nephritis. The purpose of this study was to examine the expression and function of laminins and their interactions with nucleosomes in the kidneys of patients with lupus nephritis, using surface plasmon resonance (SPR) analysis.Methods. SPR interaction analysis was used to quantify the strength of laminin-nucleosome interactions. Electron microscopy techniques were used to determine in vivo colocalization of IgG, chromatin, and laminin ␤1, as well as to characterize nucleosomelaminin interactions in vitro.Results. Nucleosomes were found to possess high affinity for laminin ␤1-containing laminins and to have the potential to form stable molecular complexes with these structures. In vivo, laminin ␤1 was aberrantly expressed in the glomerular basement membrane (GMB) of lupus nephritis patients, and in situ, it acted as a nucleosome ligand, selectively colocalizing with nucleosomes within electron-dense deposits (EDDs). Normal adult laminin 11, which contains laminin ␤2, did not bind nucleosomes, and it did not colocalize in vivo with the nucleosomes in the nephritic GBM. In addition, TGF␤1 was expressed by the glomerular mesangium, glomerular endothelial cells, and by podocytes in patients with lupus nephritis. It was trapped in situ within EDDs by an as-yet-unknown ligand. As was recently described in a transgenic mouse model, paracrine kidney glomerular TGF␤1 may thereby contribute to the development of glomerulopathy via the induction of laminin ␤1 incorporation in the GBM, whereas systemic blood vessel-derived TGF␤1 could be trapped during filtration.Conclusion. Our findings of the specific highaffinity binding of nucleosomes to aberrantly expressed laminin ␤1 in the GBM and their colocalization in the GBM may explain important features of the initial steps in the pathogenesis of lupus nephritis, the planted antigen hypothesis.

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“…Several recent studies on the BCR have indicated that Ag cross-linking induces Ig dissociation from the Ig␣␤ heterodimer (55,56). Whereas nearly all of the surface Ig is internalized, up to 30% of the Ig␣␤ heterodimers remain on the PM and continue to signal.…”

Section: Discussionmentioning

confidence: 99%

Precursor B Cell Receptor Signaling Activity Can Be Uncoupled from Surface Expression

Güloğlu¹,

Roman

2006

The Journal of Immunology

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Signals from the precursor BCR (preBCR) cause proliferation and differentiation of progenitor (pro-) B cells into pre-B cells. Given the very low amounts of surface preBCRs and the demonstrated cell autonomy of preBCR signaling, we examined the possible occurrence of preBCR signal propagation from intracellular membranes such as the endoplasmic reticulum (ER) and the trans-Golgi network (TGN) in transformed and primary pro-B cells. PreBCRs composed of normal Ig μ or truncated Dμ heavy chains (HCs) were redirected to intracellular sites via localization sequences appended to the HC cytoplasmic tail. PreBCR complexes retained in the TGN or shunted from the TGN to lysosomes were as or 50% as active as the corresponding wild-type preBCRs in directing preBCR-dependent events, including CD2 and CD22 expression and proliferation in primary pro-B cells. This occurred despite their low to undetectable surface expression in transformed cells, which otherwise allowed significant surface accumulation of wild-type preBCRs. In contrast, ER-retained preBCRs were inactive. These results suggest that preBCR signaling is remarkably tolerant of dramatic changes in its subcellular distribution within post-ER compartments and support the possibility that the preBCR can activate signaling pathways in the TGN as well as the plasma membrane.

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Independent Trafficking of Ig-α/Ig-β and μ-Heavy Chain Is Facilitated by Dissociation of the B Cell Antigen Receptor Complex

Cited by 29 publications

References 39 publications

CD20 Homo-oligomers Physically Associate with the B Cell Antigen Receptor

CD20 Homo-oligomers Physically Associate with the B Cell Antigen Receptor

Pathogenic Mechanisms in Lupus Nephritis: Nucleosomes Bind Aberrant Laminin β1 With High Affinity and Colocalize in the Electron‐Dense Deposits

Precursor B Cell Receptor Signaling Activity Can Be Uncoupled from Surface Expression

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