Cis and trans regulatory mechanisms control AP2-mediated B cell receptor endocytosis via select tyrosine-based motifs

Following antigen recognition, B cell receptor (BCR)-mediated endocytosis is the first step of antigen processing and presentation to CD4+ T cells, a crucial component of the initiation and control of the humoral immune response. Despite this, the molecular mechanism of BCR internalization is poorly...

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Bibliographic Details
Published in:PloS one 2013-01, Vol.8 (1), p.e54938-e54938
Main Authors: Busman-Sahay, Kathleen, Drake, Lisa, Sitaram, Anand, Marks, Michael, Drake, James R
Format: Article
Language:English
Subjects:
Adaptor Protein Complex 2 - metabolism
Amino Acid Motifs
Amino Acid Sequence
Animals
Antigen presentation
Antigen processing
Antigens
B cells
B-cell lymphoma
B-cell receptor
Binding
Biology
CD4 antigen
CD79 Antigens - chemistry
CD79 Antigens - metabolism
Clathrin
Coated pits
Coated Pits, Cell-Membrane - metabolism
Coated Pits, Cell-Membrane - ultrastructure
Control
Endocytosis
Immune response
Immune response (humoral)
Immune system
Immunology
Immunoreceptor tyrosine-based activation motif
Internalization
Kinases
Laboratories
Lymphocytes
Lymphocytes B
Lymphocytes T
Lymphoma
Lymphomas
Medicine
Mice
Molecular Sequence Data
Mutation
Phenols (Class of compounds)
Phosphorylation
Physiology
Pits
Protein Binding
Proteins
Receptors, Antigen, B-Cell - chemistry
Receptors, Antigen, B-Cell - metabolism
Regulatory mechanisms (biology)
Regulatory sequences
T cell receptors
T cells
Tyrosine
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Summary:Following antigen recognition, B cell receptor (BCR)-mediated endocytosis is the first step of antigen processing and presentation to CD4+ T cells, a crucial component of the initiation and control of the humoral immune response. Despite this, the molecular mechanism of BCR internalization is poorly understood. Recently, studies of activated B cell-like diffuse large B cell lymphoma (ABC DLBCL) have shown that mutations within the BCR subunit CD79b leads to increased BCR surface expression, suggesting that CD79b may control BCR internalization. Adaptor protein 2 (AP2) is the major mediator of receptor endocytosis via clathrin-coated pits. The BCR contains five putative AP2-binding YxxØ motifs, including four that are present within two immunoreceptor tyrosine-based activation motifs (ITAMs). Using a combination of in vitro and in situ approaches, we establish that the sole mediator of AP2-dependent BCR internalization is the membrane proximal ITAM YxxØ motif in CD79b, which is a major target of mutation in ABC DLBCL. In addition, we establish that BCR internalization can be regulated at a minimum of two different levels: regulation of YxxØ AP2 binding in cis by downstream ITAM-embedded DCSM and QTAT regulatory elements and regulation in trans by the partner cytoplasmic domain of the CD79 heterodimer. Beyond establishing the basic rules governing BCR internalization, these results illustrate an underappreciated role for ITAM residues in controlling clathrin-dependent endocytosis and highlight the complex mechanisms that control the activity of AP2 binding motifs in this receptor system.
ISSN:1932-6203
1932-6203
DOI:10.1371/journal.pone.0054938