DataSheet1_Ena/VASP proteins at the crossroads of actin nucleation pathways in dendritic cell migration.PDF

As sentinels of our immune system dendritic cells (DCs) rely on efficient cell migration for patrolling peripheral tissues and delivering sampled antigens to secondary lymphoid organs for the activation of T-cells. Dynamic actin polymerization is key to their macropinocytic and migratory properties. Both major actin nucleation machineries, formins and the Arp2/3 complex, are critical for different aspects of DC functionality, by driving the generation of linear and branched actin filaments, respectively. However, the importance of a third group of actin nucleators, the Ena/VASP family, has not been addressed yet. Here, we show that the two family members Evl and VASP are expressed in murine DCs and that their loss negatively affects DC macropinocytosis, spreading, and migration. Our interactome analysis reveals Ena/VASP proteins to be ideally positioned for orchestrating the different actin nucleation pathways by binding to the formin mDia1 as well as to the WAVE regulatory complex, a stimulator of Arp2/3. In fact, Evl/VASP deficient murine DCs are more vulnerable to inhibition of Arp2/3 demonstrating that Ena/VASP proteins contribute to the robustness and efficiency of DC migration.

作为免疫系统的哨兵，树突状细胞（dendritic cells, DCs）依赖高效的细胞迁移来巡逻外周组织，并将采集到的抗原递送至次级淋巴器官以激活T细胞。动态肌动蛋白聚合是其巨胞饮与迁移特性的核心基础。两类核心肌动蛋白成核装置——formin家族（formins）与Arp2/3复合物（Arp2/3 complex）——可分别介导线性与分支状肌动蛋白丝的形成，进而对树突状细胞功能的不同方面起到关键调控作用。然而，第三类肌动蛋白成核因子——Ena/VASP家族（Ena/VASP family）——的重要性迄今尚未得到阐明。本研究证实，小鼠树突状细胞中表达该家族的两个成员Evl与VASP，且二者的缺失会对树突状细胞的巨胞饮、铺展与迁移能力产生负面影响。我们的相互作用组（interactome）分析结果显示，Ena/VASP蛋白可通过结合formin家族成员mDia1，以及作为Arp2/3复合物激活因子的WAVE调节复合物（WAVE regulatory complex），实现对不同肌动蛋白成核通路的统筹调控。事实上，缺失Evl/VASP的小鼠树突状细胞对Arp2/3复合物的抑制更为敏感，这表明Ena/VASP蛋白有助于提升树突状细胞迁移的稳健性与效率。