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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Interaction of the Wiskott-Aldrich syndrome protein with sorting nexin 9 is required for CD28 endocytosis and cosignaling in T cells
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Interaction of the Wiskott-Aldrich syndrome protein with sorting nexin 9 is required for CD28 endocytosis and cosignaling in T cells

机译：Wiskott-Aldrich综合征蛋白与分选nexin 9的相互作用是CD28内吞和T细胞共信号传递所必需的

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摘要

The Wiskott-Aldrich syndrome protein (WASp) plays a major role in coupling T cell antigen receptor (TCR) stimulation to induction of actin cytoskeletal changes required for T cell activation. Here, we report that WASp inducibly binds the sorting nexin 9 (SNX9) in T cells and that WASp, SNX9, p85, and CD28 colocalize within clathrin-containing endocytic vesicles after TCR/CD28 costimulation. SNX9, implicated in clathrin-mediated endocytosis, binds WASp via its SH3 domain and uses its PX domain to interact with the phosphoinositol 3-kinase regulatory subunit p85 and product, phosphoinositol (3,4,5)P_3. The data reveal ligationinduced CD28 endocytosis to be clathrin- and phosphoinositol 3-kinase-dependent and TCR/CD28-evoked CD28 internalization and NFAT activation to be markedly enhanced by SNX9 overex-pression, but severely impaired by expression of an SNX9 mutant (SNX9APX) lacking p85-binding capacity. CD28 endocytosis and CD28-evoked actin polymerization also are impaired in WASp-deficient T cells. These findings suggest that SNX9 couples WASp to p85 and CD28 so as to link CD28 engagement to its internalization and to WASp-mediated actin remodeling required for CD28 cosignaling. Thus, the WASp/SNX9/p85/CD28 complex enables a unique interface of endocytic, actin polymerizing, and signal trans-duction pathways required for CD28-mediated T cell costimulation.
机译：Wiskott-Aldrich综合征蛋白（WASp）在偶联T细胞抗原受体（TCR）刺激与诱导T细胞活化所需的肌动蛋白细胞骨架变化中起主要作用。在这里，我们报道WASp诱导性结合T细胞中的排序神经毒素9（SNX9），并且在TCR / CD28协同刺激后，WASp，SNX9，p85和CD28共定位在含网格蛋白的内吞囊泡中。参与网格蛋白介导的内吞作用的SNX9通过其SH3结构域结合WASp，并使用其PX结构域与磷酸肌醇3-激酶调节亚基p85和产物磷酸肌醇（3,4,5）P_3相互作用。数据显示，连接诱导的CD28内吞作用是网格蛋白和磷酸肌醇3激酶依赖性的，TCR / CD28引起的CD28内在化和NFAT激活会因SNX9过表达而显着增强，但会因SNX9突变体（SNX9APX）的表达而严重受损。缺乏p85结合能力。在WASp缺陷型T细胞中，CD28内吞作用和CD28诱发的肌动蛋白聚合也受到损害。这些发现表明，SNX9将WASp与p85和CD28结合，从而将CD28的参与与其内在化以及CD28共信号传递所需的WASp介导的肌动蛋白重塑联系起来。因此，WASp / SNX9 / p85 / CD28复合物可实现CD28介导的T细胞共刺激所需的内吞，肌动蛋白聚合和信号转导途径的独特界面。

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