BCR ubiquitination controls BCR-mediated antigen processing and presentation.
BCR-mediated antigen processing occurs at immunologically relevant antigen concentrations and hinges on the trafficking of antigen-BCR (Ag-BCR) complexes to class II-containing multivesicular bodies (MVBs) termed MIICs. However, the molecular mechanism underlying the trafficking of Ag-BCR complexes to and within MIICs is not well understood. In contrast, the trafficking of the epidermal growth factor receptor (EGFR) to and within MVBs occurs via a well-characterized ubiquitin-dependent mechanism, which is blocked by acute inhibition of proteasome activity. Using a highly characterized antigen-specific model system, it was determined that the immunoglobulin heavy chain subunit of the IgM BCR of normal (ie, nontransformed) B cells is ubiquitinated. Moreover, acute inhibition of proteasome activity delays the formation of ubiquitinated ligand-BCR complexes, alters the intracellular trafficking of internalized Ag-BCR complexes, and selectively blocks the BCR-mediated processing and presentation of cognate antigen, without inhibiting the endocytosis, processing, and presentation of non-cognate antigen internalized by fluidphase endocytosis. These results demonstrate that the trafficking of Ag-BCR complexes to and within MVB-like antigen processing compartments occurs via a molecular mechanism with similarities to that used by the EGFR, and establishes the EGFR as a paradigm for the further analysis of Ag-BCR trafficking to and within MIICs.
Drake
Lisa
L
Albany Medical College, Center for Immunology and Microbial Disease, 47 New Scotland Ave, MC-151, Albany, NY 12208, USA. drakej@mail.amc.edu
McGovern-Brindisi
Erica M
EM
Drake
James R
JR
D000818:Animals; D017951:Antigen Presentation / Q000276:immunology*; D001402:B-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D004705:Endocytosis / Q000276:immunology; D066246:ErbB Receptors / Q000276:immunology / Q000378:metabolism; D007075:Immunoglobulin M / Q000276:immunology* / Q000378:metabolism; D051379:Mice; D046988:Proteasome Endopeptidase Complex / Q000276:immunology / Q000378:metabolism; D011499:Protein Processing, Post-Translational / Q000276:immunology*; D021381:Protein Transport / Q000276:immunology; D025801:Ubiquitin / Q000276:immunology* / Q000378:metabolism
D007075:Immunoglobulin M; D025801:Ubiquitin; D066246:ErbB Receptors; D046988:Proteasome Endopeptidase Complex