A role for lysosomal-associated protein transmembrane 5 in the negative regulation of surface B cell receptor levels and B cell activation.
Mechanisms by which cell surface levels of the BCR are regulated remain largely unknown. We found that B cells lacking the lysosomal-associated protein transmembrane 5 (LAPTM5) expressed higher levels of cell surface BCR than did wild-type (WT) B cells after Ag stimulation in vitro and in vivo. In addition, LAPTM5-deficient mice contained an increased frequency of Ag-specific B cells and produced greater amounts of Abs than did WT mice after immunization with a T-dependent Ag. Adoptive transfer of LAPTM5-deficient B cells with WT T cells into RAG1-deficient mice revealed that the increased surface BCR levels and the enhanced B cell activation and Ab production were due to a B cell intrinsic defect. As they aged, the LAPTM5-deficient mice had increased titers of serum IgM and autoantibodies and immune complex deposition in the kidney. Immunofluorescent and biochemical analysis revealed that LAPTM5 physically interacted with the BCR complex and promoted its degradation in the lysosomal compartment in mouse B cells. These results demonstrate a role for LAPTM5 in the negative regulation of cell surface BCR levels and B cell activation.
Laboratory for Immune Diversity, Research Center for Allergy and Immunology, RIKEN Yokohama Institute, Yokohama, Japan.
Rika
R
Ouchida
Tomohiro
T
Kurosaki
Ji-Yang
JY
Wang
D000818:Animals; D000915:Antibody Affinity; D016175:B-Lymphocyte Subsets / Q000201:enzymology / Q000276:immunology* / Q000378:metabolism*; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D002645:Chickens; D015536:Down-Regulation / Q000276:immunology*; D018985:Epitopes, B-Lymphocyte / Q000276:immunology; D006241:Haptens / Q000008:administration & dosage / Q000276:immunology / Q000378:metabolism; D017874:Immediate-Early Proteins / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D007075:Immunoglobulin M / Q000096:biosynthesis / Q000378:metabolism; D008213:Lymphocyte Activation / Q000276:immunology*; D008247:Lysosomes / Q000201:enzymology*; D008565:Membrane Proteins / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D009596:Nitrophenols / Q000008:administration & dosage / Q000276:immunology / Q000378:metabolism; D010648:Phenylacetates / Q000008:administration & dosage / Q000276:immunology / Q000378:metabolism; D011947:Receptors, Antigen, B-Cell / Q000037:antagonists & inhibitors* / Q000096:biosynthesis* / Q000378:metabolism; D015854:Up-Regulation / Q000276:immunology; D005719:gamma-Globulins / Q000008:administration & dosage / Q000276:immunology / Q000378:metabolism
D018985:Epitopes, B-Lymphocyte; D006241:Haptens; D017874:Immediate-Early Proteins; D007075:Immunoglobulin M; C484408:Laptm5 protein, mouse; D008565:Membrane Proteins; D009596:Nitrophenols; D010648:Phenylacetates; D011947:Receptors, Antigen, B-Cell; D005719:gamma-Globulins; C026242:4-hydroxy-5-nitrophenyl acetic acid