Cdc42 regulates neutrophil migration via crosstalk between WASp, CD11b, and microtubules
Cdc42 regulates neutrophil migration via crosstalk between WASp, CD11b, and microtubules
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DOI：
10.1182/blood-2012-04-426981
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发表时间：
2012-10-25
期刊：
影响因子：
20.3
通讯作者：
Filippi, Marie-Dominique
中科院分区：
文献类型：
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作者：
Kumar, Sachin;Xu, Juying;Filippi, Marie-Dominique
趋化性通过使中性粒细胞迁移到感染组织来促进中性粒细胞参与细胞防御，并受到持续细胞极化的控制。中性粒细胞极性的一个长期存在的问题是伪足和尾足如何协调。在我们之前的报告中，我们认为 Rho GTPase Cdc42 通过尾足的 CD11b 信号传导控制中性粒细胞极性，尽管机制未知。在这里，我们展示了 Cdc42 通过其效应器 WASp 意外地控制极性。 Cdc42 控制 WASp 激活及其对尾足动物的远程定位。在尾足动物中，WASp 调节 CD11b 整合素重组为耐去污剂的膜结构域；反过来，CD11b 招募微管末端结合蛋白 EB1 来捕获并稳定尾足的微管。该组织对于在迁移过程中维持中性粒细胞极性是必要的，并且对于中性粒细胞迁移到发炎的肺部至关重要。这些结果表明中性粒细胞极性的机制尚未被认识，其中 WASp 介导 Cdc42 对尾足的远距离控制，以维持伪足和尾足之间的适当平衡。我们的研究揭示了 WASp 通过 CD11b 和微管之间的串扰控制中性粒细胞极性的新功能。 （血。2012；120(17):3563-3574）
Chemotaxis promotes neutrophil participation in cellular defense by enabling neutrophil migration to infected tissue and is controlled by persistent cell polarization. One long-standing question of neutrophil polarity has been how the pseudopod and the uropod are coordinated. In our previous report, we suggested that Rho GTPase Cdc42 controls neutrophil polarity through CD11b signaling at the uropod, albeit through an unknown mechanism. Here, we show that Cdc42 controls polarity, unexpectedly, via its effector WASp. Cdc42 controls WASp activation and its distant localization to the uropod. At the uropod, WASp regulates the reorganization of CD11b integrin into detergent resistant membrane domains; in turn, CD11b recruits the microtubule end binding protein EB1 to capture and stabilize microtubules at the uropod. This organization is necessary to maintain neutrophil polarity during migration and is critical for neutrophil emigration into inflamed lungs. These results suggest unrecognized mechanism of neutrophil polarity in which WASp mediates long-distance control of the uropod by Cdc42 to maintain a proper balance between the pseudopod and the uropod. Our study reveals a new function for WASp in the control of neutrophil polarity via crosstalk between CD11b and microtubules. (Blood. 2012;120(17):3563-3574)