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Dictates the Endocytic Fate of the B Cell Antigen Receptor1
,¶
,
* Section of Rheumatology, Department of Medicine,
Committee on Immunology,
Department of Pathology,
Ben May Institute for Cancer Research, and
¶ Biochemistry and Molecular Biology, University of Chicago, IL 60637;
|| Department of Microbiology-Immunology,
# Division of Molecular Oncology, Department of Medicine, Evanston Northwestern Healthcare Research Institute, Feinberg School of Medicine, and
** Department of Biochemistry, Molecular Biology and Cell Biology, and Robert H. Lurie Comprehensive Cancer Center, Northwestern University, Evanston, IL 60211
In both infection and autoimmunity, the development of high-affinity Abs and memory requires B cells to efficiently capture and process Ags for presentation to cognate T cells. Although a great deal is known about how Ags are processed, the molecular mechanisms by which the BCR captures Ag for processing are still obscure. In this study, we demonstrate that the Ig
component of the BCR is diubiquitinylated and that this is dependent on the E3 ligase Itch. Itch–/– B lymphocytes manifest both a defect in ligand-induced BCR internalization and endocytic trafficking to late endosomal Ag-processing compartments. In contrast, analysis of ubiquitinylation-defective receptors demonstrated that the attachment of ubiquitins to Ig is required for endosomal sorting and for the presentation of Ag to T cells, yet, ubiquitinylation is dispensable for receptor internalization. Membrane-bound Igµ was not detectably ubiquitinylated nor were the conserved lysines in the mu cytosolic tail required for trafficking to late endosomes. These results demonstrate that ubiquitinylation of a singular substrate, Ig, is required for a specific receptor trafficking event. However, they also reveal that E3 ligases play a broader role in multiple processes that determine the fate of Ag-engaged BCR complexes.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This work was supported by grants from the National Institutes of Health (to M.R.C.: GM52736, GM067772; to H.B.: CA87986, CA76119, CA99900, CA99163) and the Arthritis Foundation (to M.R.C.). H.B. acknowledges support from the Jean Ruggles-Romoser Chair for Cancer Research.
2 Address correspondence and reprint requests to Dr. Marcus R. Clark, Section of Rheumatology, Department of Medicine, University of Chicago, 5841 South Maryland Avenue, Room N005B, Chicago, IL 60637. E-mail address: mclark{at}medicine.bsd.uchicago.edu
3 Abbreviations used in this paper: IMB, intraluminal multivesicular body; Ub, ubiquitin; HECT, homologous to the E6-associated protein C terminus; RING, really interesting new gene; STAM, signal-transducing adaptor molecule; WT, wild type; PDGF, platelet-derived growth factor; BS3, Bis-(sulfosuccinimidyl) suberate; OGP, n-octyl--D-glucopyranoside; mIg, membrane-bound Ig; VHS, Vps27-h-STAM; UIM, Ub-interacting motif; LMP, latent membrane protein; Tf, transferrin; SLAP, Src-like adaptor protein.
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  S. K. O'Neill, M. L. Veselits, M. Zhang, C. Labno, Y. Cao, A. Finnegan, M. Uccellini, M.-L. Alegre, J. C. Cambier, and M. R. Clark Endocytic sequestration of the B cell antigen receptor and toll-like receptor 9 in anergic cells PNAS, April 14, 2009; 106(15): 6262 - 6267. [Abstract] [Full Text] [PDF]
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