Destabilization of Long Astral Microtubules via Cdk1-Dependent Removal of GTSE1 from Their Plus Ends Facilitates Prometaphase Spindle Orientation
Destabilization of Long Astral Microtubules via Cdk1-Dependent Removal of GTSE1 from Their Plus Ends Facilitates Prometaphase Spindle Orientation
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DOI：
10.1016/j.cub.2020.11.040
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发表时间：
2021-02-22
期刊：
影响因子：
9.2
通讯作者：
Bird, Alexander W.
中科院分区：
文献类型：
--
作者：
Singh, Divya;Schmidt, Nadine;Bird, Alexander W.
在细胞分裂过程中，微管动力学在时间和空间上的精确调节对于最终使细胞增殖、组织和发育的几种有丝分裂机制至关重要。从中心体向细胞皮质延伸的星形微管必须存在，才能使有丝分裂纺锤体正确定向，并忠实地执行后期和胞质分裂。然而，关于星形微管的动态特性是如何在时空上调节的，或者星形微管动力学对纺锤体定位的贡献，人们知之甚少。有丝分裂调节因子CDK1-CyclinB促进中心体微管的失稳和细胞进入有丝分裂时微管动力学的增加，但CDK1活性如何调节星形微管的稳定性，以及它是否影响纺锤体的定位，目前尚不清楚。在这里，我们揭示了一种机制，揭示了CDK1在早中期破坏星形微管的稳定，从而影响纺锤体的重新定位。在有丝分裂早期，依赖于EB1的微管+末端跟踪蛋白GTSE1被CDK1磷酸化，取消了它与EB1的相互作用，并重新聚集到微管+末端。CDK1活性的丧失或GTSE1磷酸化位点的突变，导致GTSE1重新聚集到生长中的微管和有丝分裂的末端。这降低了星形微管的突变频率，并导致到达细胞皮质的长星形微管数量增加，这抑制了细胞在早期有丝分裂中沿长细胞轴重新定向纺锤体的能力。因此，星体微管不仅必须存在，而且必须是动态的，以允许纺锤体重新定向，这种状态是通过CDK1选择性地使长星体微管失稳而辅助的。
The precise regulation of microtubule dynamics over time and space in dividing cells is critical for several mitotic mechanisms that ultimately enable cell proliferation, tissue organization, and development. Astral microtubules, which extend from the centrosome toward the cell cortex, must be present for themitotic spindle to properly orient, as well as for the faithful execution of anaphase and cytokinesis. However, little is understood about how the dynamic properties of astral microtubules are regulated spatiotemporally, or the contribution of astral microtubule dynamics to spindle positioning. The mitotic regulator Cdk1-CyclinB promotes destabilization of centrosomal microtubules and increased microtubule dynamics as cells enter mitosis, but how Cdk1 activity modulates astral microtubule stability, and whether it impacts spindle positioning, is unknown. Here, we uncover a mechanismrevealing that Cdk1 destabilizes astral microtubules in prometaphase and thereby influences spindle reorientation. Phosphorylation of the EB1-dependent microtubule plus-end tracking protein GTSE1 by Cdk1 in early mitosis abolishes its interaction with EB1 and recruitment to microtubule plus ends. Loss of Cdk1 activity, or mutation of phosphorylation sites in GTSE1, induces recruitment of GTSE1 to growing microtubule plus ends in mitosis. This decreases the catastrophe frequency of astral microtubules and causes an increase in the number of long astral microtubules reaching the cell cortex, which restrains the ability of cells to reorient spindles along the long cellular axis in early mitosis. Astral microtubules thus must not only be present but also dynamic to allow the spindle to reorient, a state assisted by selective destabilization of long astral microtubules via Cdk1.