title: Cofilin-mediated F-actin severing is regulated by the Rap GTPase and controls the cytoskeletal dynamics that drive lymphocyte spreading and BCR microcluster formation.
abstract: When lymphocytes encounter APCs bearing cognate Ag, they spread across the surface of the APC to scan for additional Ags. This is followed by membrane contraction and the formation of Ag receptor microclusters that initiate the signaling reactions that lead to lymphocyte activation. Breakdown of the submembrane cytoskeleton is likely to be required for the cytoskeleton reorganization that drives cell spreading and for removing physical barriers that limit Ag receptor mobility. In this report, we show that Ag receptor signaling via the Rap GTPases promotes the dephosphorylation and activation of the actin-severing protein cofilin and that this results in increased severing of cellular actin filaments. Moreover, we show that this cofilin-mediated actin severing is critical for the changes in actin dynamics that drive B and T cell spreading, for the formation of BCR microclusters, and for the increased mobility of BCR microclusters within the plasma membrane after BCR engagement. Finally, using a model APC, we show that activation of this Rap-cofilin signaling module controls the amount of Ag that is gathered into BCR microclusters and that this is directly related to the magnitude of the resulting BCR signaling that is initiated during B cell-APC interactions. Thus, Rap-dependent activation of cofilin is critical for the early cytoskeletal changes and BCR reorganization that are involved in APC-dependent lymphocyte activation.
authors: Department of Microbiology and Immunology, I³ and Cell and Developmental Biology Research Groups, Life Sciences Institute, University of British Columbia, Vancouver, British Columbia V6T 1Z3, Canada.
authors: Spencer A
authors: SA
authors: Freeman
authors: Victor
authors: V
authors: Lei
authors: May
authors: M
authors: Dang-Lawson
authors: Kensaku
authors: K
authors: Mizuno
authors: Calvin D
authors: CD
authors: Roskelley
authors: Michael R
authors: MR
authors: Gold
mesh_terms: D051339:Actin Depolymerizing Factors / Q000276:immunology / Q000378:metabolism*; D000199:Actins / Q000276:immunology / Q000378:metabolism*; D000818:Animals; D017951:Antigen Presentation / Q000276:immunology; D001402:B-Lymphocytes / Q000276:immunology / Q000378:metabolism; D002634:Chemotaxis, Leukocyte / Q000276:immunology*; D003599:Cytoskeleton / Q000276:immunology / Q000378:metabolism; D003713:Dendritic Cells / Q000276:immunology; D005455:Fluorescent Antibody Technique; D020558:GTP Phosphohydrolases / Q000276:immunology / Q000378:metabolism*; D015151:Immunoblotting; D008213:Lymphocyte Activation / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D005810:Multigene Family; D011947:Receptors, Antigen, B-Cell / Q000276:immunology / Q000378:metabolism*; D013601:T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D014162:Transfection
chemical_list: D051339:Actin Depolymerizing Factors; D000199:Actins; D011947:Receptors, Antigen, B-Cell; D020558:GTP Phosphohydrolases