title: Recruitment of Cbl-b to B cell antigen receptor couples antigen recognition to Toll-like receptor 9 activation in late endosomes.
abstract: Casitas B-lineage lymphoma-b (Cbl-b) is a ubiquitin ligase (E3) that modulates signaling by tagging molecules for degradation. It is a complex protein with multiple domains and binding partners that are not involved in ubiquitinating substrates. Herein, we demonstrate that Cbl-b, but not c-Cbl, is recruited to the clustered B cell antigen receptor (BCR) and that Cbl-b is required for entry of endocytosed BCRs into late endosomes. The E3 activity of Cbl-b is not necessary for BCR endocytic trafficking. Rather, the ubiquitin associated (UBA) domain is required. Furthermore, the Cbl-b UBA domain is sufficient to confer the receptor trafficking functions of Cbl-b on c-Cbl. Cbl-b is also required for entry of the Toll-like receptor 9 (TLR9) into late endosomes and for the in vitro activation of TLR9 by BCR-captured ligands. These data indicate that Cbl-b acts as a scaffolding molecule to coordinate the delivery of the BCR and TLR9 into subcellular compartments required for productively delivering BCR-captured ligands to TLR9.
authors.affiliation: Section of Rheumatology, Department of Medicine and Knapp Center for Lupus and Immunological Research, University of Chicago, Chicago, Illinois, United States of America.
authors.forename: Margaret
authors.initials: M
authors.lastname: Veselits
authors.affiliation: Section of Rheumatology, Department of Medicine and Knapp Center for Lupus and Immunological Research, University of Chicago, Chicago, Illinois, United States of America.
authors.forename: Azusa
authors.initials: A
authors.lastname: Tanaka
authors.affiliation: Laboratory of Cellular and Molecular Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, United States of America.
authors.forename: Stanley
authors.initials: S
authors.lastname: Lipkowitz
authors.affiliation: Integrated Department of Immunology, National Jewish Medical and Research Center and University of Colorado and Health Sciences Center, Denver, Colorado, United States of America.
authors.forename: Shannon
authors.initials: S
authors.lastname: O'Neill
authors.affiliation: Section of Rheumatology, Department of Medicine and Knapp Center for Lupus and Immunological Research, University of Chicago, Chicago, Illinois, United States of America.
authors.forename: Roger
authors.initials: R
authors.lastname: Sciammas
authors.affiliation: Department of Immunology and Microbiology, and Department of Internal Medicine, Section of Rheumatology, Rush University Medical Center, Chicago, Illinois, United States of America.
authors.forename: Alison
authors.initials: A
authors.lastname: Finnegan
authors.affiliation: Section of Nephrology, Department of Medicine, University of Chicago, Chicago, Illinois, United States of America.
authors.forename: Jian
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Section of Rheumatology, Department of Medicine and Knapp Center for Lupus and Immunological Research, University of Chicago, Chicago, Illinois, United States of America.
authors.forename: Marcus R
authors.initials: MR
authors.lastname: Clark
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000737:chemistry / Q000378:metabolism*; D000818:Animals; D000941:Antigens / Q000276:immunology*; D004705:Endocytosis; D011992:Endosomes / Q000378:metabolism*; D006801:Humans; D008810:Mice, Inbred C57BL; D050505:Mutant Proteins / Q000378:metabolism; D017434:Protein Structure, Tertiary; D021381:Protein Transport; D050721:Proto-Oncogene Proteins c-cbl / Q000737:chemistry / Q000378:metabolism*; D011947:Receptors, Antigen, B-Cell / Q000378:metabolism*; D013154:Spleen / Q000201:enzymology; D051217:Toll-Like Receptor 9 / Q000378:metabolism*; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D000941:Antigens; C118387:Cblb protein, mouse; D050505:Mutant Proteins; D011947:Receptors, Antigen, B-Cell; C495370:Tlr9 protein, mouse; D051217:Toll-Like Receptor 9; C492211:CBLB protein, human; D050721:Proto-Oncogene Proteins c-cbl; D044767:Ubiquitin-Protein Ligases