Cenp-F links kinetochores to Ndel1/Nde1/Lis1/Dynein microtubule motor complexes
Cenp-F links kinetochores to Ndel1/Nde1/Lis1/Dynein microtubule motor complexes
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DOI：
10.1016/j.cub.2007.05.077
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发表时间：
2007-07-03
期刊：
影响因子：
9.2
通讯作者：
Taylor, Stephen S.
中科院分区：
文献类型：
--
作者：
Vergnolle, Mailys A. S.;Taylor, Stephen S.
CENP-F是一种核基质成分，在有丝分裂期间定位于着丝点，有丝分裂后迅速降解[1]。不同寻常的是，CENP-F的定位和降解都需要将其法尼化[2]。最近的五项研究表明，CENP-F是动粒-微管相互作用和纺锤体检查点功能所必需的[3-7]；然而，其潜在的分子机制尚未确定。在这里，我们证明了CENP-F与Ndel1和NDE1相互作用，这两个人类裸体相关蛋白参与调节Lis1/Dynein马达复合体(在[8]中综述)。我们证明了Ndel1、Ndel和Lis1以CENP-F依赖的方式定位于运动中枢。此外，Dynein的动粒定位需要NDE1，而不是Ndel1。因此，抑制ndel会抑制中期染色体的排列，并激活纺锤体检查点。相比之下，抑制Ndel1会导致纺锤体检查点无法检测到的定向错误；Ndel1缺陷的细胞因此会及时进入后期，但落后的染色体随后就会出现。因此，CENP-F的一个主要功能是将Ndel1/NDE1/Lis1/Dynein通路与动点连接起来。此外，我们的数据表明，Ndell和Ndel在确保染色体比对和分离方面发挥着不同的作用。
Cenp-F is a nuclear matrix component that localizes to kinetochores during mitosis and is then rapidly degraded after mitosis [1]. Unusually, both the localization and degradation of Cenp-F require it to be farnesylated [2]. Five studies recently demonstrated that Cenp-F is required for kinetochore-microtubule interactions and spindle checkpoint function [3-7]; however, the underlying molecular mechanisms have yet to be defined. Here, we show that Cenp-F interacts with Ndel1 and Nde1, two human NudE-related proteins implicated in regulating Lis1/Dynein motor complexes (reviewed in [8]). We show that Ndel1, Ndel, and Lis1 localize to kinetochores in a Cenp-F-dependent manner. In addition, Nde1, but not Ndel1, is required for kinetochore localization of Dynein. Accordingly, suppression of Ndel inhibits metaphase chromosome alignment and activates the spindle checkpoint. By contrast, inhibition of Ndel1 results in malorientations that are not detected by the spindle checkpoint; Ndel1-deficient cells consequently enter anaphase in a timely manner but lagging chromosomes then manifest. A major function of Cenp-F, therefore, is to link the Ndel1/Nde1/Lis1/Dynein pathway to kinetochores. Furthermore, our data demonstrate that Ndell and Ndel play distinct roles to ensure chromosome alignment and segregation.