Diverse mitotic functions of the cytoskeletal cross-linking protein Shortstop suggest a role in Dynein/Dynactin activity.
Diverse mitotic functions of the cytoskeletal cross-linking protein Shortstop suggest a role in Dynein/Dynactin activity.
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DOI：
10.1091/mbc.e17-04-0219
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发表时间：
2017-09-15
影响因子：
3.3
通讯作者：
Johnston CA
中科院分区：
文献类型：
--
作者：
Dewey EB;Johnston CA
Shortstop （Shot）是一种肌动蛋白-微管交联蛋白，与动态肌动蛋白成分Arp-1相互作用，控制果蝇有丝分裂纺锤体的组装和定位。孢子对染色体的聚合和分离起着重要的作用。上皮组织中Shot的缺失会导致显著的细胞凋亡，当细胞凋亡被阻断时，会导致上皮-间质过渡样变化。双极有丝分裂纺锤体的正确组装和定向对细胞分裂的保真度至关重要。有丝分裂的精确性从根本上决定了细胞的命运、组织的发育和稳态以及子细胞内的染色体分布。这些事件中的缺陷被认为是导致几种人类疾病的原因。然而，纺锤体形态发生和定位的潜在机制仍未完全确定。在这里，我们描述了肌动蛋白-微管交联剂Shortstop （Shot）在果蝇有丝分裂纺锤体功能中的不同作用。Shot定位于有丝分裂的纺锤极，它的击倒导致纺锤极形态不聚焦和正常纺锤方向的破坏。Shot缺失还会导致染色体聚集缺陷、细胞周期进展延迟和后期染色体分离缺陷。这些有丝分裂错误触发果蝇上皮组织的凋亡，阻断这种凋亡反应导致上皮-间质转化标记物MMP-1的显著诱导。Shot的肌动蛋白结合域直接与肌动蛋白相关蛋白-1 （Arp-1）相互作用，Arp-1是Dynein/Dynactin复合物的关键成分。Arp-1表型的下调引起了普遍的射击损失，而f -肌动蛋白的化学破坏则是选择性的。我们的工作强调了Shot在有丝分裂中的新作用，并提出了一种涉及动力蛋白/动力蛋白激活的机制。
Shortstop (Shot), an actin–microtubule cross-linking protein, interacts with the Dynactin component Arp-1 to control mitotic spindle assembly and positioning in Drosophila. Shot is important for proper chromosome congression and segregation. Loss of Shot in epithelial tissue leads to significant apoptosis, which when blocked leads to epithelial–mesenchymal transition-like changes. Proper assembly and orientation of the bipolar mitotic spindle is critical to the fidelity of cell division. Mitotic precision fundamentally contributes to cell fate specification, tissue development and homeostasis, and chromosome distribution within daughter cells. Defects in these events are thought to contribute to several human diseases. The underlying mechanisms that function in spindle morphogenesis and positioning remain incompletely defined, however. Here we describe diverse roles for the actin-microtubule cross-linker Shortstop (Shot) in mitotic spindle function in Drosophila. Shot localizes to mitotic spindle poles, and its knockdown results in an unfocused spindle pole morphology and a disruption of proper spindle orientation. Loss of Shot also leads to chromosome congression defects, cell cycle progression delay, and defective chromosome segregation during anaphase. These mitotic errors trigger apoptosis in Drosophila epithelial tissue, and blocking this apoptotic response results in a marked induction of the epithelial–mesenchymal transition marker MMP-1. The actin-binding domain of Shot directly interacts with Actin-related protein-1 (Arp-1), a key component of the Dynein/Dynactin complex. Knockdown of Arp-1 phenocopies Shot loss universally, whereas chemical disruption of F-actin does so selectively. Our work highlights novel roles for Shot in mitosis and suggests a mechanism involving Dynein/Dynactin activation.