NDP52 tunes cortical actin interaction with astral microtubules for accurate spindle orientation
NDP52 tunes cortical actin interaction with astral microtubules for accurate spindle orientation
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DOI：
10.1038/s41422-019-0189-9
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发表时间：
2019-06
期刊：
影响因子：
44.1
通讯作者：
Huijuan Yu;Fengrui Yang;Peng Dong;S. Liao;Wei Liu;Gangyin Zhao;Bo Qin;Zhen Dou;Zhe Liu;Wei Liu;J. Zang;J. Lippincott-Schwartz;Xing Liu;X. Yao
中科院分区：
文献类型：
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作者：
Huijuan Yu;Fengrui Yang;Peng Dong;S. Liao;Wei Liu;Gangyin Zhao;Bo Qin;Zhen Dou;Zhe Liu;Wei Liu;J. Zang;J. Lippincott-Schwartz;Xing Liu;X. Yao
定向细胞分裂受GαI、LGN和NUMA等保守的分子级联调控。在这里，我们展示了NDP52通过重塑极皮质肌动蛋白细胞骨架来调节纺锤体的方向。SiRNA介导的NDP52抑制令人惊讶地发现，在前期/早中期细胞中，纺锤体周围有致密的环状皮质下F-肌动蛋白构筑，导致星形微管生长严重缺陷和纺锤体取向异常。值得注意的是，NDP52招募了肌动蛋白组装因子N-WASP，并调节了有丝分裂细胞皮质下F-肌动蛋白环的动态。在机制上，NDP52被发现与含有磷脂酸的小泡结合，后者吸收细胞质中的N-WASP来调节极皮层局部丝状肌动蛋白的生长。我们的TIRFM分析表明，在体外，含有NDP52的囊泡锚定了N-WASP并缩短了肌动蛋白细丝的长度。基于这些结果，我们认为含有NDP52的囊泡通过N-WASP来调节皮质肌动蛋白的动力学，从而完成星形微管和肌动蛋白网络之间的时空调节，从而实现正确的纺锤体定位和精确的染色体分离。通过这种方式，细胞内的小泡与微管和肌动蛋白细丝合作，调节适当的有丝分裂进程。由于酵母中不存在NDP52，我们推测后生动物已经进化出一种复杂的纺锤体定位机制，以确保有丝分裂中准确的染色体分离。
Oriented cell divisions are controlled by a conserved molecular cascade involving Gαi, LGN, and NuMA. Here, we show that NDP52 regulates spindle orientation via remodeling the polar cortical actin cytoskeleton. siRNA-mediated NDP52 suppression surprisingly revealed a ring-like compact subcortical F-actin architecture surrounding the spindle in prophase/prometaphase cells, which resulted in severe defects of astral microtubule growth and an aberrant spindle orientation. Remarkably, NDP52 recruited the actin assembly factor N-WASP and regulated the dynamics of the subcortical F-actin ring in mitotic cells. Mechanistically, NDP52 was found to bind to phosphatidic acid-containing vesicles, which absorbed cytoplasmic N-WASP to regulate local filamentous actin growth at the polar cortex. Our TIRFM analyses revealed that NDP52-containing vesicles anchored N-WASP and shortened the length of actin filaments in vitro. Based on these results we propose that NDP52-containing vesicles regulate cortical actin dynamics through N-WASP to accomplish a spatiotemporal regulation between astral microtubules and the actin network for proper spindle orientation and precise chromosome segregation. In this way, intracellular vesicles cooperate with microtubules and actin filaments to regulate proper mitotic progression. Since NDP52 is absent from yeast, we reason that metazoans have evolved an elaborate spindle positioning machinery to ensure accurate chromosome segregation in mitosis.