Actin-binding protein 1 and Dynamin-2 modulate attenuation of B-cell signaling and regulate B-cell function

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dc.contributor.advisorSong, Wenxiaen_US
dc.contributor.authorSeeley-Fallen, Margaret Kathrynen_US
dc.contributor.departmentCell Biology & Molecular Geneticsen_US
dc.contributor.publisherDigital Repository at the University of Marylanden_US
dc.contributor.publisherUniversity of Maryland (College Park, Md.)en_US
dc.date.accessioned2015-02-07T06:30:35Z
dc.date.available2015-02-07T06:30:35Z
dc.date.issued2014en_US
dc.description.abstractB-cells mediate humoral immune responses with production of an amazingly diverse repertoire of antigen specific antibodies. Antigen binding to the B-cell receptor (BCR) induces coordinated BCR signaling and BCR-mediated antigen internalization, processing, and presentation to helper T-cells, necessary for generation of humoral memory. Prolonged or uncontrolled BCR signaling has been linked to development of autoimmunity; therefore controlled attenuation of B-cell signaling is required for maintenance of B-cell tolerance. This study investigates the role of an actin adaptor protein, actin-binding protein 1 (Abp1/HIP-55/SH3P7), in BCR-mediated signal transduction and subsequent B-cell function. I found that in both Abp1-/- and Abp1-/--bone marrow chimeric mice, in which only B-cells lack Abp1 expression, the number of spontaneous germinal center and marginal zone B-cells, and levels of autoantibody are significantly increased. Serum levels of T-independent antibody and total IgM and IgG antibodies are elevated in Abp1-/- mice, whereas T-dependent IgG responses are reduced and fail to undergo affinity maturation. Upon binding membrane-associated antigen, surface BCR clustering is enhanced and B-cell contraction delayed in Abp1-/- B cells, concurrent with slow but persistent increases in F-actin at BCR signalosomes. Furthermore, BCR signaling is enhanced in Abp1-/- B cells, including Ca2+ flux and phosphorylation of B-cell linker protein (BLNK), mitogen-activated protein kinase kinase MEK1/2, and extracellular signal-regulated kinase (ERK), coinciding with reductions in recruitment of the inhibitory signaling molecules, hematopoietic progenitor kinase 1 (HPK1) and SH2-containing inositol 5-phosphatase (SHIP-1) to BCR signalosomes. Our previous studies demonstrated a role for Abp1 in BCR internalization by linking the actin cytoskeleton to the endocytic machinery protein dynamin2. This study shows that dyanmin2 is recruited to the BCR upon antigen binding, and its recruitment is dependent on its proline rich domain (PRD). BCR internalization and trafficking to late endosomes requires the PRD, GTPase function, and tyrosine phosphorylation sites of dynamin2. B-cells expressing a GTPase dead mutant of dynamin2 exhibit enhanced BCR clustering and signaling. These results indicate Abp1 negatively regulates BCR signaling by coupling actin remodeling to B-cell contraction, activation of inhibitory signaling molecules, and the endocytic machinery protein dynamin2, revealing a novel regulatory mechanism for peripheral B-cell development and antibody response.en_US
dc.identifierhttps://doi.org/10.13016/M2B315
dc.identifier.urihttp://hdl.handle.net/1903/16251
dc.language.isoenen_US
dc.subject.pqcontrolledCellular biologyen_US
dc.subject.pqcontrolledMolecular biologyen_US
dc.subject.pquncontrolledActin-binding protein 1en_US
dc.subject.pquncontrolledActin cytoskeletonen_US
dc.subject.pquncontrolledB-lymphocytesen_US
dc.subject.pquncontrolledDynamin-2en_US
dc.subject.pquncontrolledSignaling transductionen_US
dc.titleActin-binding protein 1 and Dynamin-2 modulate attenuation of B-cell signaling and regulate B-cell functionen_US
dc.typeDissertationen_US

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