title: Ezrin tunes the magnitude of humoral immunity.
abstract: Ezrin is a member of the ezrin-radixin-moesin family of membrane-actin cytoskeleton cross-linkers that participate in a variety of cellular processes. In B cells, phosphorylation of ezrin at different sites regulates multiple processes, such as lipid raft coalescence, BCR diffusion, microclustering, and endosomal JNK activation. In this study, we generated mice with conditional deletion of ezrin in the B cell lineage to investigate the physiological significance of ezrin's function in Ag receptor-mediated B cell activation and humoral immunity. B cell development, as well as the proportion and numbers of major B cell subsets in peripheral lymphoid organs, was unaffected by the loss of ezrin. Using superresolution imaging methods, we show that, in the absence of ezrin, BCRs respond to Ag binding by accumulating into larger and more stable signaling microclusters. Loss of ezrin led to delayed BCR capping and accelerated lipid raft coalescence. Although proximal signaling proteins showed stronger activation in the absence of ezrin, components of the distal BCR signaling pathways displayed distinct effects. Ezrin deficiency resulted in increased B cell proliferation and differentiation into Ab-secreting cells ex vivo and stronger T cell-independent and -dependent responses to Ag in vivo. Overall, our data demonstrate that ezrin regulates amplification of BCR signals and tunes the strength of B cell activation and humoral immunity.
authors.affiliation: Department of Immunology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195;
authors.forename: Debasis
authors.initials: D
authors.lastname: Pore
authors.forename: Neetha
authors.initials: N
authors.lastname: Parameswaran
authors.forename: Ken
authors.initials: K
authors.lastname: Matsui
authors.forename: Matthew B
authors.initials: MB
authors.lastname: Stone
authors.forename: Ichiko
authors.initials: I
authors.lastname: Saotome
authors.forename: Andrea I
authors.initials: AI
authors.lastname: McClatchey
authors.forename: Sarah L
authors.initials: SL
authors.lastname: Veatch
authors.forename: Neetu
authors.initials: N
authors.lastname: Gupta
mesh_terms: D008841:Actin Cytoskeleton / Q000276:immunology / Q000378:metabolism; D000818:Animals; D016175:B-Lymphocyte Subsets / Q000276:immunology* / Q000378:metabolism; D001402:B-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D002454:Cell Differentiation / Q000276:immunology; D002462:Cell Membrane / Q000276:immunology / Q000378:metabolism; D049109:Cell Proliferation; D003598:Cytoskeletal Proteins / Q000235:genetics / Q000378:metabolism*; D056724:Immunity, Humoral; D008213:Lymphocyte Activation / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010766:Phosphorylation; D011947:Receptors, Antigen, B-Cell / Q000276:immunology*; D015398:Signal Transduction / Q000276:immunology; D000099149:Ezrin
chemical_list: D003598:Cytoskeletal Proteins; D011947:Receptors, Antigen, B-Cell; D000099149:Ezrin
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