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Proc Natl Acad Sci U S A. 2014 Jul 8;111(27):9881-6. doi: 10.1073/pnas.1321971111. Epub 2014 Jun 23.

Actin-binding protein 1 links B-cell antigen receptors to negative signaling pathways.

Author information

1
Department of Cell Biology and Molecular Genetics, University of Maryland, College Park, MD 20742;
2
Laboratory of Translational Genomics, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892;
3
Laboratory of Immunology, Virginia-Maryland Regional College of Veterinary Medicine, University of Maryland, College Park, MD 20742;
4
Department of Pathology and Immunology, Baylor College of Medicine, Houston, TX 77030; and.
5
Department of Physics, University of Maryland, College Park, MD 20742.
6
Department of Cell Biology and Molecular Genetics, University of Maryland, College Park, MD 20742; wenxsong@umd.edu.

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.

KEYWORDS:

B-lymphocytes; actin cytoskeleton; signal transduction

PMID:
24958882
PMCID:
PMC4103327
DOI:
10.1073/pnas.1321971111
[Indexed for MEDLINE]
Free PMC Article

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