title: Actin-binding protein 1 links B-cell antigen receptors to negative signaling pathways.
abstract: Prolonged or uncontrolled B-cell receptor (BCR) signaling is associated with autoimmunity. We previously demonstrated a role for actin in BCR signal attenuation. This study reveals that actin-binding protein 1 (Abp1/HIP-55/SH3P7) is a negative regulator of BCR signaling and links actin to negative regulatory pathways of the BCR. In both Abp1(-/-) and bone marrow chimeric mice, in which only B cells lack Abp1 expression, the number of spontaneous germinal center and marginal zone B cells and the level of autoantibody are significantly increased. Serum levels of T-independent antibody responses and total antibody are elevated, whereas T-dependent antibody responses are markedly reduced and fail to undergo affinity maturation. Upon activation, 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 compared with wild-type B cells, including Ca(2+) flux and phosphorylation of B-cell linker protein, the mitogen-activated protein kinase kinase MEK1/2, and ERK, coinciding with reductions in recruitment of the inhibitory signaling molecules hematopoietic progenitor kinase 1 and SH2-containing inositol 5-phosphatase to BCR signalosomes. Our results indicate that Abp1 negatively regulates BCR signaling by coupling actin remodeling to B-cell contraction and activation of inhibitory signaling molecules, which contributes to the regulation of peripheral B-cell development and antibody responses.
authors: Department of Cell Biology and Molecular Genetics, University of Maryland, College Park, MD 20742;
authors: Margaret K
authors: MK
authors: Seeley-Fallen
authors: Department of Cell Biology and Molecular Genetics, University of Maryland, College Park, MD 20742;
authors: Lisa J
authors: LJ
authors: Liu
authors: Department of Cell Biology and Molecular Genetics, University of Maryland, College Park, MD 20742;
authors: Melanie R
authors: MR
authors: Shapiro
authors: Laboratory of Translational Genomics, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892;
authors: Olusegun O
authors: OO
authors: Onabajo
authors: Laboratory of Immunology, Virginia-Maryland Regional College of Veterinary Medicine, University of Maryland, College Park, MD 20742;
authors: Senthilkumar
authors: S
authors: Palaniyandi
authors: Laboratory of Immunology, Virginia-Maryland Regional College of Veterinary Medicine, University of Maryland, College Park, MD 20742;
authors: Xiaoping
authors: X
authors: Zhu
authors: Department of Pathology and Immunology, Baylor College of Medicine, Houston, TX 77030; and.
authors: Tse-Hua
authors: TH
authors: Tan
authors: Department of Physics, University of Maryland, College Park, MD 20742.
authors: Arpita
authors: A
authors: Upadhyaya
authors: Department of Cell Biology and Molecular Genetics, University of Maryland, College Park, MD 20742; wenxsong@umd.edu.
authors: Wenxia
authors: W
authors: Song
mesh_terms: D000818:Animals; D000906:Antibodies / Q000097:blood; D001402:B-Lymphocytes / Q000166:cytology; D018858:Germinal Center / Q000166:cytology; D000072181:Inositol Polyphosphate 5-Phosphatases; D051379:Mice; D018345:Mice, Knockout; D008840:Microfilament Proteins / Q000235:genetics / Q000378:metabolism*; D010744:Phosphoric Monoester Hydrolases / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D011947:Receptors, Antigen, B-Cell / Q000378:metabolism*; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000276:immunology
chemical_list: D000906:Antibodies; D008840:Microfilament Proteins; D011947:Receptors, Antigen, B-Cell; C102102:hematopoietic progenitor kinase 1; D017346:Protein Serine-Threonine Kinases; D010744:Phosphoric Monoester Hydrolases; D000072181:Inositol Polyphosphate 5-Phosphatases
keywords: B-lymphocytes; actin cytoskeleton; signal transduction