N-WASP Is Essential for the Negative Regulation of B Cell Receptor Signaling

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N-WASP Is Essential for the Negative Regulation of B Cell Receptor Signaling

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Title: N-WASP Is Essential for the Negative Regulation of B Cell Receptor Signaling
Author: Liu, Chaohong; Bai, Xiaoming; Wu, Junfeng; Sharma, Shruti; Upadhyaya, Arpita; Dahlberg, Carin I. M.; Westerberg, Lisa S.; Snapper, Scott B.; Zhao, Xiaodong; Song, Wenxia

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Citation: Liu, Chaohong, Xiaoming Bai, Junfeng Wu, Shruti Sharma, Arpita Upadhyaya, Carin I. M. Dahlberg, Lisa S. Westerberg, Scott B. Snapper, Xiaodong Zhao, and Wenxia Song. 2013. “N-WASP Is Essential for the Negative Regulation of B Cell Receptor Signaling.” PLoS Biology 11 (11): e1001704. doi:10.1371/journal.pbio.1001704. http://dx.doi.org/10.1371/journal.pbio.1001704.
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Abstract: Negative regulation of receptor signaling is essential for controlling cell activation and differentiation. In B-lymphocytes, the down-regulation of B-cell antigen receptor (BCR) signaling is critical for suppressing the activation of self-reactive B cells; however, the mechanism underlying the negative regulation of signaling remains elusive. Using genetically manipulated mouse models and total internal reflection fluorescence microscopy, we demonstrate that neuronal Wiskott–Aldrich syndrome protein (N-WASP), which is coexpressed with WASP in all immune cells, is a critical negative regulator of B-cell signaling. B-cell–specific N-WASP gene deletion causes enhanced and prolonged BCR signaling and elevated levels of autoantibodies in the mouse serum. The increased signaling in N-WASP knockout B cells is concurrent with increased accumulation of F-actin at the B-cell surface, enhanced B-cell spreading on the antigen-presenting membrane, delayed B-cell contraction, inhibition in the merger of signaling active BCR microclusters into signaling inactive central clusters, and a blockage of BCR internalization. Upon BCR activation, WASP is activated first, followed by N-WASP in mouse and human primary B cells. The activation of N-WASP is suppressed by Bruton's tyrosine kinase-induced WASP activation, and is restored by the activation of SH2 domain-containing inositol 5-phosphatase that inhibits WASP activation. Our results reveal a new mechanism for the negative regulation of BCR signaling and broadly suggest an actin-mediated mechanism for signaling down-regulation.
Published Version: doi:10.1371/journal.pbio.1001704
Other Sources: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3818172/pdf/
Terms of Use: This article is made available under the terms and conditions applicable to Other Posted Material, as set forth at http://nrs.harvard.edu/urn-3:HUL.InstRepos:dash.current.terms-of-use#LAA
Citable link to this page: http://nrs.harvard.edu/urn-3:HUL.InstRepos:11879183
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