The Syk-binding Ubiquitin Ligase c-Cbl Mediates Signaling-dependent B Cell Receptor Ubiquitination and B Cell Receptor-mediated Antigen Processing and Presentation

Bhuvana Katkere,Sarah Rosa,James R Drake

doi:10.1074/jbc.m112.357640

Bhuvana Katkere, Sarah Rosa + Show 1 more

Open Access

https://doi.org/10.1074/jbc.m112.357640

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Abstract

B cell receptor (BCR)-mediated antigen (Ag) processing and presentation lead to B cell-T cell interactions, which support affinity maturation and immunoglobulin class switching. These interactions are supported by generation of peptide-MHC class II complexes in multivesicular body-like MIIC compartments of B cells. Previous studies have shown that trafficking of Ag·BCR complexes to MVB-like MIIC occurs via an ubiquitin-dependent pathway and that ubiquitination of Ag·BCR complexes occurs by an Src family kinase signaling-dependent mechanism that is restricted to lipid raft-resident Ag·BCR complexes. This study establishes that downstream Syk-dependent BCR signaling is also required for BCR ubiquitination and BCR-mediated antigen processing and presentation. Knockdown studies reveal that of the two known Syk-binding E3 ubiquitin ligases c-Cbl and Cbl-b, only c-Cbl appears to have a central role in BCR ubiquitination, trafficking to MIIC, and ubiquitin-dependent BCR-mediated antigen processing and presentation. These results establish the novel role for Syk signaling and the Syk-binding ubiquitin ligase c-Cbl in the BCR-mediated processing and presentation of cognate antigen and define one mechanism by which antigen-induced BCR ubiquitination is modulated to impact the initiation and maturation of the humoral immune response.

Highlights

B lymphocytes are unique antigen-presenting cells in that they are the only antigen-presenting cells with a clonotypically restricted antigen binding receptor, the B cell receptor (BCR)2
Binding of antigen to the BCR results in Ag1⁄7BCR endocytosis and trafficking to multivesicular body (MVB)-like MIIC where Ag1⁄7BCR complexes are processed to peptides that are loaded onto MHC class II molecules for presentation to CD4 T cells (9 –14)
BCR ubiquitination, which is critical for the trafficking of Ag1⁄7BCR complexes to MVB-like antigen processing compartments, occurs via an Src-family kinase-dependent mechanism and is restricted to lipid raft-resident Ag1⁄7BCR complexes [18, 31]

Summary

Introduction

B lymphocytes are unique antigen-presenting cells in that they are the only antigen-presenting cells with a clonotypically restricted antigen binding receptor, the B cell receptor (BCR)2. These results define the mechanism by which c-Cbl functions to coordinate antigen-induced BCR signaling and ubiquitination as well as the rapid processing and presentation of Ag1⁄7BCR complexes to support the development of the humoral immune response.

Results

Conclusion