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Sci. Signal., 31 July 2012
Vol. 5, Issue 235, p. ra54
[DOI: 10.1126/scisignal.2002820]

RESEARCH ARTICLES

The Scaffolding Protein Synapse-Associated Protein 97 Is Required for Enhanced Signaling Through Isotype-Switched IgG Memory B Cell Receptors

Wanli Liu1,2, Elizabeth Chen1*, Xing Wang Zhao2*, Zheng Peng Wan2*, Yi Ren Gao2*, Angel Davey1*, Eric Huang1, Lijia Zhang1, Jillian Crocetti3,4, Gabriel Sandoval5, M. Gordon Joyce1, Carrie Miceli3,4, Jan Lukszo6, L. Aravind7, Wojciech Swat5, Joseph Brzostowski1, and Susan K. Pierce1{dagger}

1 Laboratory of Immunogenetics, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville, MD 20852, USA.
2 School of Life Sciences, Tsinghua University, 100084 Beijing, China.
3 Microbiology, Immunology and Molecular Genetics, School of Medicine and College of Letters and Sciences, University of California, Los Angeles, 277B Biomedical Sciences Research Building, 615 Charles E. Young Drive South, Los Angeles, CA 90095, USA.
4 Molecular Biology Institute, University of California, Los Angeles, 611 Charles E. Young Drive East, Los Angeles, CA 90095, USA.
5 Department of Pathology and Immunology, Washington University School of Medicine, 660 South Euclid Avenue, St. Louis, MO 63110, USA.
6 Peptide Synthesis and Analysis Laboratory, Research Technologies Branch, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville, MD 20852, USA.
7 National Center for Biotechnology Information, National Library of Medicine, National Institutes of Health, Bethesda, MD 20894, USA.

* These authors contributed equally to this work.

Abstract: After their first encounter with a foreign antigen, naïve B cells that have immunoglobulin M (IgM) B cell receptors (BCRs) trigger the primary antibody response and the generation of memory B cells with IgG BCRs. When these memory B cells reencounter the same antigen, the cell surface IgG BCRs stimulate their rapid differentiation into plasma cells that release large amounts of IgG antibodies. We showed that the conserved cytoplasmic tail of the IgG BCR, which contains a putative PDZ (postsynaptic density 95/disc large/zona occludens 1)–binding motif, associated with synapse-associated protein 97 (SAP97), a PDZ domain–containing scaffolding molecule that is involved in controlling receptor density and signal strength at neuronal synapses. SAP97 accumulated and bound to IgG BCRs in the immunological synapses that formed in response to B cell engagement with antigen. Knocking down SAP97 in IgG+ B cells or mutating the putative PDZ-binding motif in the BCR tail impaired formation of the immunological synapse, initiation of IgG BCR signaling, and downstream activation of the mitogen-activated protein kinase p38. Thus, heightened B cell memory responses are encoded, in part, by a mechanism that involves SAP97 serving as a scaffolding protein in the IgG BCR immunological synapse.

{dagger} To whom correspondence should be addressed. E-mail: spierce{at}nih.gov

Citation: W. Liu, E. Chen, X. W. Zhao, Z. P. Wan, Y. R. Gao, A. Davey, E. Huang, L. Zhang, J. Crocetti, G. Sandoval, M. G. Joyce, C. Miceli, J. Lukszo, L. Aravind, W. Swat, J. Brzostowski, S. K. Pierce, The Scaffolding Protein Synapse-Associated Protein 97 Is Required for Enhanced Signaling Through Isotype-Switched IgG Memory B Cell Receptors. Sci. Signal. 5, ra54 (2012).

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