Ubiquitinylation of Ig beta dictates the endocytic fate of the B cell antigen receptor.
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 beta 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 beta is required for endosomal sorting and for the presentation of Ag to T cells, yet, ubiquitinylation is dispensable for receptor internalization. Membrane-bound Ig mu 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 beta, 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.
Zhang
Miao
M
Section of Rheumatology, Department of Medicine, University of Chicago, IL 60637, USA.
Veselits
Margaret
M
O'Neill
Shannon
S
Hou
Ping
P
Reddi
Alagarsamy L
AL
Berlin
Ilana
I
Ikeda
Masato
M
Nash
Piers D
PD
Longnecker
Richard
R
Band
Hamid
H
Clark
Marcus R
MR
D000595:Amino Acid Sequence; D000818:Animals; D017951:Antigen Presentation / Q000276:immunology; D001402:B-Lymphocytes / Q000378:metabolism; D001483:Base Sequence; D001692:Biological Transport; D045744:Cell Line, Tumor; D004705:Endocytosis / Q000276:immunology*; D011992:Endosomes / Q000378:metabolism; D007136:Immunoglobulins / Q000737:chemistry / Q000145:classification / Q000276:immunology* / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D008969:Molecular Sequence Data; D011485:Protein Binding; D011947:Receptors, Antigen, B-Cell / Q000276:immunology* / Q000378:metabolism*; D013154:Spleen / Q000378:metabolism; D013601:T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D013997:Time Factors; D025801:Ubiquitin / Q000378:metabolism*; D044767:Ubiquitin-Protein Ligases / Q000172:deficiency / Q000235:genetics / Q000378:metabolism
D007136:Immunoglobulins; D011947:Receptors, Antigen, B-Cell; D025801:Ubiquitin; C471637:Itch protein, mouse; D044767:Ubiquitin-Protein Ligases