Lipid Raft-Independent B Cell Receptor-Mediated Antigen Internalization and Intracellular Trafficking

Putnam, Michelle A.; Moquin, Amy; Merrihew, Megan; Outcalt, Christopher; Sorge, Emily; Caballero, Adriana; Gondré-Lewis, Timothy; Drake, James R.

doi:10.4049/jimmunol.170.2.905

Cited by 44 publications

(58 citation statements)

References 35 publications

(43 reference statements)

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“…Indeed, we find that complete inhibition of PI3K signaling has little effect on BCR endocytosis in mouse B cells (data not shown). Results from other studies indicate that the requirements for lipid rafts, tyrosine kinases, and actin cytoskeleton in BCR internalization vary depending on the nature of the Ag and B cells (12,13,61), and the present data suggest that uptake of soluble Ags by primary B cells may not be highly dependent on signaling via PI3K, Bam32, and Rac.…”

Section: Discussionmentioning

confidence: 49%

Bam32/DAPP1 Promotes B Cell Adhesion and Formation of Polarized Conjugates with T Cells

Al‐Alwan¹,

Hou²,

Zhang

et al. 2010

The Journal of Immunology

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B cell Ag receptors function in both signaling activation of Ag-specific cells and in collecting specific Ag for presentation to T lymphocytes. Signaling via PI3K is required for BCR-mediated activation and Ag presentation functions; however, the relevant downstream targets of PI3K in B cells are incompletely defined. In this study, we have investigated the roles of the PI3K effector molecule Bam32/DAPP1 in BCR signaling and BCR-mediated Ag presentation functions. In mouse primary B cells, Bam32 was required for efficient activation of the GTPase Rac1 and downstream signaling to JNK, but not activation of BLNK, phospholipase C γ2, or calcium responses. Consistent with a role of this adaptor in Rac-mediated cytoskeletal rearrangement, Bam32 was required for BCR-induced cell adhesion and spreading responses on ICAM-1 or fibronectin-coated surfaces. The function of Bam32 in promoting Rac activation and adhesion required tyrosine 139, a known site of phosphorylation by Lyn kinase. After BCR crosslinking by Ag, Bam32-deficient B cells are able to carry out the initial steps of Ag endocytosis and processing, but show diminished ability to form Ag-specific conjugates with T cells and polarize F-actin at the B-T interface. As a result, Bam32-deficient B cells were unable to efficiently activate Ag-specific T cells. Together, these results indicate that Bam32 serves to integrate PI3K and Src kinase signaling to promote Rac-dependent B cell adhesive interactions important for Ag presentation function.

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Section: Discussionmentioning

confidence: 49%

Bam32/DAPP1 Promotes B Cell Adhesion and Formation of Polarized Conjugates with T Cells

Al‐Alwan¹,

Hou²,

Zhang

et al. 2010

The Journal of Immunology

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“…This proposes that receptor-mediated endocytosis occurs through a subset of clathrin that is constitutively associated with lipid rafts. These conclusions were questioned, however, when it was shown that the extent of BCR endocytosis was not affected by the disruption of lipid rafts, demonstrating that the bulk of Ag-bound receptors is internalized through a pathway independent of lipid rafts (11). Furthermore, this study suggested that raftassociated receptors had a different intracellular itinerary than the majority of receptors internalized through CCVs.…”

mentioning

confidence: 88%

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

Kim

Cramer

Mueller

et al. 2005

The Journal of Immunology

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The BCR relays extracellular signals and internalizes Ag for processing and presentation. We have previously demonstrated that ligation of the BCR destabilizes Ig-α/Ig-β (Ig-αβ) from μ-H chain (μm). In this study we report that receptor destabilization represents a physical separation of μm from Ig-αβ. Sucrose gradient fractionation localized Ig-αβ to GM1-containing lipid microdomains in the absence of μm. Confocal and electron microscopy studies revealed the colocalization of unsheathed μm with clathrin-coated vesicles. Furthermore, μm failed to associate with clathrin-coated vesicles when receptor destabilization was inhibited, suggesting that unsheathing of μm is required for clathrin-mediated endocytosis. In summary, we found that Ag stimulation physically separates Ig-αβ from μm, facilitating concomitant signal transduction and Ag delivery to the endocytic compartment.

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“…Surprisingly, this effect was rather specific, because the expression of the costimulatory receptor CD28 was slightly increased, whereas the expression of the glycosylphosphatidylinositol-linked protein CD59 was unaffected. Glycosylphosphatidylinositol-linked proteins and antigen receptor complexes utilize different internalization pathways (41,42), suggesting that HIP-55 is specifically involved in clathrincoated vesicle trafficking. Supporting this notion is our observation that expression of HIP-55 in kidney cells is required during transferrin receptor endocytosis (25).…”

Section: Discussionmentioning

confidence: 99%

Recruitment of the Actin-binding Protein HIP-55 to the Immunological Synapse Regulates T Cell Receptor Signaling and Endocytosis

Bras

Foucault

Foussat

et al. 2004

Journal of Biological Chemistry

109

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Actin cytoskeleton dynamics critically regulate T cell activation. We found that the cytoplasmic adaptor HIP-55, a Src/Syk-kinases substrate and member of the drebrin/Abp1 family of actin-binding proteins, localized to the T cell-antigen-presenting cell (APC) contact site in an antigen-dependent manner. Using green fluorescent protein fusion proteins, both Src homology 3 (SH3) and actin binding domains were found necessary for recruitment at the T cell-APC interface. HIP-55 was not implicated in conjugate formation and actin polymerization but regulated distal signaling events through binding and activation of hematopoietic progenitor kinase 1 (HPK1), a germinal center kinase (GCK) family kinase involved in negative signaling in T cells. Using RNA interference and overexpression experiments, the HIP-55-HPK1 complex was found to negatively regulate nuclear factor of activated T cell (NFAT) activation by the T cell antigen receptor. Moreover, we show that HIP-55, which partly co-localized with early endocytic compartments, promoted both basal and ligand-dependent T cell receptor (TCR) down-modulation, resulting in a decreased TCR expression. SH3 and actin-depolymerizing factor homology domains were required for this function. As controls, the expression of CD28 and the glycosylphosphatidylinositol-linked protein CD59 was not affected by HIP-55 overexpression. These results suggest that, in addition to binding to HPK1, HIP-55 might negatively regulate TCR signaling through down-regulation of TCR expression. Our findings show that HIP-55 is a key novel component of the immunological synapse that modulates T cell activation by connecting actin cytoskeleton and TCRs to gene activation and endocytic processes.

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Lipid Raft-Independent B Cell Receptor-Mediated Antigen Internalization and Intracellular Trafficking

Cited by 44 publications

References 35 publications

Bam32/DAPP1 Promotes B Cell Adhesion and Formation of Polarized Conjugates with T Cells

Bam32/DAPP1 Promotes B Cell Adhesion and Formation of Polarized Conjugates with T Cells

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

Recruitment of the Actin-binding Protein HIP-55 to the Immunological Synapse Regulates T Cell Receptor Signaling and Endocytosis

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