Lymphocyte Interaction Laboratory, London Research Institute, Cancer Research UK, London WC2A 3PX, England, UK.
J Exp Med. 2011 May 9;208(5):1055-68. doi: 10.1084/jem.20101125. Epub 2011 Apr 11.
Signaling microclusters are a common feature of lymphocyte activation. However, the mechanisms controlling the size and organization of these discrete structures are poorly understood. The Ezrin-Radixin-Moesin (ERM) proteins, which link plasma membrane proteins with the actin cytoskeleton and regulate the steady-state diffusion dynamics of the B cell receptor (BCR), are transiently dephosphorylated upon antigen receptor stimulation. In this study, we show that the ERM proteins ezrin and moesin influence the organization and integrity of BCR microclusters. BCR-driven inactivation of ERM proteins is accompanied by a temporary increase in BCR diffusion, followed by BCR immobilization. Disruption of ERM protein function using dominant-negative or constitutively active ezrin constructs or knockdown of ezrin and moesin expression quantitatively and qualitatively alters BCR microcluster formation, antigen aggregation, and downstream BCR signal transduction. Chemical inhibition of actin polymerization also altered the structure and integrity of BCR microclusters. Together, these findings highlight a crucial role for the cortical actin cytoskeleton during B cell spreading and microcluster formation and function.
信号微簇是淋巴细胞激活的一个共同特征。然而，控制这些离散结构的大小和组织的机制还了解甚少。埃兹蛋白（Ezrin-Radixin-Moesin，ERM）将质膜蛋白与肌动蛋白细胞骨架连接起来，并调节 B 细胞受体（BCR）的稳态扩散动力学，在抗原受体刺激时会被短暂去磷酸化。在这项研究中，我们表明 ERM 蛋白 ezrin 和 moesin 影响 BCR 微簇的组织和完整性。ERM 蛋白的 BCR 驱动失活伴随着 BCR 扩散的暂时增加，随后是 BCR 固定。使用显性负性或组成性激活的 ezrin 构建体或敲低 ezrin 和 moesin 表达来破坏 ERM 蛋白功能，在数量和质量上改变了 BCR 微簇的形成、抗原聚集和下游 BCR 信号转导。肌动蛋白聚合的化学抑制也改变了 BCR 微簇的结构和完整性。总之，这些发现强调了在 B 细胞扩展和微簇形成和功能过程中，皮质肌动蛋白细胞骨架的关键作用。
