WHAMY is a novel actin polymerase promoting myoblast fusion, macrophage cell motility and sensory organ development in Drosophila
WHAMY is a novel actin polymerase promoting myoblast fusion, macrophage cell motility and sensory organ development in Drosophila
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DOI：
10.1242/jcs.179325
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发表时间：
2016-02-01
影响因子：
4
通讯作者：
Bogdan, Sven
中科院分区：
文献类型：
--
作者：
Brinkmann, Klaus;Winterhoff, Moritz;Bogdan, Sven
Wiskott-Aldrich综合征蛋白(Wasp)是差异控制Arp2/3复合体的核促进因子(NPF)。在果蝇中，到目前为止，已经分析了三个不同的家庭成员，SCAR(也被称为Wave)，WASP和WASH(也被称为CG13176)。在这里，我们描述了果蝇WASP家族的第四个成员WHAMY。Whamy起源于黄蜂基因的复制，并经历了亚新功能化。与WASP不同的是，我们发现WHAMY通过其两个婴儿床结构域与激活的rac1特异性地相互作用，这两个结构域足以将WHAMY靶向板脂和丝足尖。生化分析表明，WHAMY促进了极快的肌动蛋白细丝伸长，尽管它不激活Arp2/3复合体。功能丧失和功能获得的研究揭示了WHAMY在巨噬细胞的膜突起和细胞迁移中的重要作用。遗传数据进一步表明WHAMY和WASP在形态发生过程中具有协同作用。双突变体具胚胎晚期致死性，成肌细胞融合存在严重缺陷。反式杂合子突变动物在感觉细胞命运规范方面表现出强烈的缺陷。因此，WHAMY是一种新的肌动蛋白聚合酶，在发育过程中对祖先的WASP功能进行初始划分，并在进化过程中随后获得新的细胞运动功能。
Wiskott-Aldrich syndrome proteins (WASPs) are nucleation-promoting factors (NPF) that differentially control the Arp2/3 complex. In Drosophila, three different family members, SCAR (also known as WAVE), WASP and WASH (also known as CG13176), have been analyzed so far. Here, we characterized WHAMY, the fourth Drosophila WASP family member. whamy originated from a wasp gene duplication and underwent a sub-neofunctionalization. Unlike WASP, we found that WHAMY specifically interacted with activated Rac1 through its two CRIB domains, which were sufficient for targeting WHAMY to lamellipodial and filopodial tips. Biochemical analyses showed that WHAMY promoted exceptionally fast actin filament elongation, although it did not activate the Arp2/3 complex. Loss-and gain-of-function studies revealed an important function of WHAMY in membrane protrusions and cell migration in macrophages. Genetic data further implied synergistic functions between WHAMY and WASP during morphogenesis. Double mutants were late-embryonic lethal and showed severe defects in myoblast fusion. Trans-heterozygous mutant animals showed strongly increased defects in sensory cell fate specification. Thus, WHAMY is a novel actin polymerase with an initial partitioning of ancestral WASP functions in development and subsequent acquisition of a new function in cell motility during evolution.