title: The Syk-binding ubiquitin ligase c-Cbl mediates signaling-dependent B cell receptor ubiquitination and B cell receptor-mediated antigen processing and presentation.
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.
authors.affiliation: Center for Immunology and Microbial Disease, Albany Medical College, Albany, New York 12208, USA.
authors.forename: Bhuvana
authors.initials: B
authors.lastname: Katkere
authors.forename: Sarah
authors.initials: S
authors.lastname: Rosa
authors.forename: James R
authors.initials: JR
authors.lastname: Drake
mesh_terms: D000818:Animals; D017951:Antigen Presentation / Q000502:physiology*; D002460:Cell Line; D000949:Histocompatibility Antigens Class II / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D006801:Humans; D056724:Immunity, Humoral / Q000502:physiology; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D051379:Mice; D011485:Protein Binding / Q000502:physiology; D021381:Protein Transport / Q000502:physiology; D011505:Protein-Tyrosine Kinases / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D050721:Proto-Oncogene Proteins c-cbl / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D011947:Receptors, Antigen, B-Cell / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology*; D000072377:Syk Kinase; D013601:T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D054875:Ubiquitination / Q000276:immunology*
chemical_list: D000949:Histocompatibility Antigens Class II; D047908:Intracellular Signaling Peptides and Proteins; D011947:Receptors, Antigen, B-Cell; D050721:Proto-Oncogene Proteins c-cbl; D011505:Protein-Tyrosine Kinases; C000606896:SYK protein, human; D000072377:Syk Kinase; C000606897:Syk protein, mouse; C493849:Cbl protein, mouse