Staccato/Unc-13-4 controls secretory lysosome-mediated lumen fusion during epithelial tube anastomosis
Staccato/Unc-13-4 controls secretory lysosome-mediated lumen fusion during epithelial tube anastomosis
复制标题
DOI：
10.1038/ncb3374
复制
发表时间：
2016-07-01
影响因子：
21.3
通讯作者：
Luschnig, Stefan
中科院分区：
文献类型：
--
作者：
Caviglia, Sara;Brankatschk, Marko;Luschnig, Stefan
在管状网络（如脉管系统）的发育过程中，一个关键但定义不清的步骤是在预先存在的管腔化管之间形成连接（血管）。通过对果蝇气管吻合的研究，我们发现了分泌型溶酶体相关细胞器（LRO）运输在管腔融合中的关键作用。我们确定保守的钙结合蛋白Unc-13-4/Staccato（Stac）和GTPase Rab 39是该过程的关键调节因子。Stac和Rab 39在动态囊泡上积累，动态囊泡仅在融合尖端细胞中形成，以动力蛋白依赖性方式移动，并含有LRO特征性的晚期内体、溶酶体和SNARE组分。GTdR Arl 3对于Stac LRO形成是必要的和足够的，并且促进并列的顶端质膜的Stac依赖性细胞内融合，从而形成跨细胞腔。同时，钙从ER出口部位局部释放，顶端膜相关钙增加。我们建议，钙依赖性集中激活LRO胞吐限制管腔融合到适当的领域内的尖端细胞。
A crucial yet ill-defined step during the development of tubular networks, such as the vasculature, is the formation of connections (anastomoses) between pre-existing lumenized tubes. By studying tracheal tube anastomosis in Drosophila melanogaster, we uncovered a key role of secretory lysosome-related organelle (LRO) trafficking in lumen fusion. We identified the conserved calcium-binding protein Unc-13-4/Staccato (Stac) and the GTPase Rab39 as critical regulators of this process. Stac and Rab39 accumulate on dynamic vesicles, which form exclusively in fusion tip cells, move in a dynein-dependent manner, and contain late-endosomal, lysosomal, and SNARE components characteristic of LROs. The GTPase Arl3 is necessary and sufficient for Stac LRO formation and promotes Stac-dependent intracellular fusion of juxtaposed apical plasma membranes, thereby forming a transcellular lumen. Concomitantly, calcium is released locally from ER exit sites and apical membrane-associated calcium increases. We propose that calcium-dependent focused activation of LRO exocytosis restricts lumen fusion to appropriate domains within tip cells.