Department of Biological Sciences, Indian Institute of Science Education and Research, Mohali, India
Laboratory of Cellular Dynamics, Regional Centre for Biotechnology, Faridabad, India.
J Cell Biol. 2019 Mar 4;218(3):871-894. doi: 10.1083/jcb.201804183. Epub 2019 Jan 23.
Hook proteins are evolutionarily conserved dynein adaptors that promote assembly of highly processive dynein-dynactin motor complexes. Mammals express three Hook paralogs, namely Hook1, Hook2, and Hook3, that have distinct subcellular localizations and expectedly, distinct cellular functions. Here we demonstrate that Hook2 binds to and promotes dynein-dynactin assembly specifically during mitosis. During the late G2 phase, Hook2 mediates dynein-dynactin localization at the nuclear envelope (NE), which is required for centrosome anchoring to the NE. Independent of its binding to dynein, Hook2 regulates microtubule nucleation at the centrosome; accordingly, Hook2-depleted cells have reduced astral microtubules and spindle positioning defects. Besides the centrosome, Hook2 localizes to and recruits dynactin and dynein to the central spindle. Dynactin-dependent targeting of centralspindlin complex to the midzone is abrogated upon Hook2 depletion; accordingly, Hook2 depletion results in cytokinesis failure. We find that the zebrafish Hook2 homologue promotes dynein-dynactin association and was essential for zebrafish early development. Together, these results suggest that Hook2 mediates assembly of the dynein-dynactin complex and regulates mitotic progression and cytokinesis.
钩蛋白是进化上保守的动力蛋白衔接物，可促进高推进力的动力蛋白-动力蛋白复合物的组装。哺乳动物表达三种 Hook 蛋白同源物，即 Hook1、Hook2 和 Hook3，它们具有不同的亚细胞定位，预计具有不同的细胞功能。在这里，我们证明 Hook2 在有丝分裂期间特异性地结合并促进动力蛋白-动力蛋白复合物的组装。在晚期 G2 期，Hook2 介导动力蛋白-动力蛋白复合物在核膜（NE）处的定位，这对于中心体锚定到 NE 是必需的。独立于其与动力蛋白的结合，Hook2 调节中心体处的微管核形成；因此，耗尽 Hook2 的细胞中星体微管减少并且纺锤体定位缺陷。除了中心体，Hook2 还定位于并募集动力蛋白和动力蛋白到中心纺锤体。耗尽 Hook2 后，dynactin 依赖性的中心纺锤体复合物向中带的靶向作用被废除；因此，耗尽 Hook2 会导致胞质分裂失败。我们发现，斑马鱼 Hook2 同源物促进动力蛋白-动力蛋白复合物的组装，并且对于斑马鱼早期发育是必需的。总之，这些结果表明 Hook2 介导了动力蛋白-动力蛋白复合物的组装，并调节有丝分裂进程和胞质分裂。
