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

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. © 2013 liu et al.