Submitted May 25, 2006
Accepted August 1, 2006
BCR ubiquitination controls BCR-mediated antigen
processing and presentation
Lisa Drake, Erica M McGovern-Brindisi, and James R Drake*
Albany Medical College, Center for Immunology and Microbial Disease, Albany, NY, USA
* Corresponding author; email: drakej{at}mail.amc.edu.
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 multi-vesicular bodies (MVB) termed MIIC. However, the molecular mechanism underlying the trafficking of Ag-BCR complexes to and within MIIC is not well understood. In contrast, the trafficking of the epidermal growth factor receptor (EGFR) to and within MVB 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 (i.e., non-transformed) 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 fluid-phase 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 utilized by the EGFR, and establishes the EGFR as a paradigm for the further analysis of Ag-BCR trafficking to and within MIIC.
