Preventing farnesylation of the dynein adaptor Spindly contributes to the mitotic defects caused by farnesyltransferase inhibitors.
Preventing farnesylation of the dynein adaptor Spindly contributes to the mitotic defects caused by farnesyltransferase inhibitors.
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DOI：
10.1091/mbc.e14-11-1560
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发表时间：
2015-05-15
影响因子：
3.3
通讯作者：
Gassmann R
中科院分区：
文献类型：
--
作者：
Holland AJ;Reis RM;Niessen S;Pereira C;Andres DA;Spielmann HP;Cleveland DW;Desai A;Gassmann R
在人类细胞中，动力蛋白适配器Spindly被鉴定为法尼基转移酶的一种新底物。法尼基化是纺锤体在着丝粒上积累所必需的，而非法尼基化的纺锤体延迟了染色体的聚集，为法尼基转移酶抑制剂的生物学效应提供了新的机理见解。对法尼基转移酶抑制剂（FTIs）的临床兴趣使得了解这些化合物如何影响涉及法尼基化蛋白的细胞过程变得非常重要。到目前为止，在用FTIs处理后观察到的有丝分裂异常归因于外动粒蛋白CENP-E和CENP-F的法尼基化缺陷，所述外动粒蛋白CENP-E和CENP-F参与染色体聚集和纺锤体组装检查点信号传导。在这里，我们确定了细胞质动力蛋白适配器纺锤体作为一个额外的组成部分，修改的外动粒法尼基转移酶（FTase）。我们发现，法尼基化的纺锤体是必不可少的，其本地化，从而为适当的本地化的动力蛋白及其辅助因子dynactin，prometaphase动粒和纺锤体动粒招聘更严重的影响FTase抑制比动粒招聘CENP-E和CENP-F。分子置换实验表明，Spindly和CENP-E法尼基化都是有效的染色体聚集所必需的。鉴定纺锤体作为FTase的新的有丝分裂底物提供了对FTase抑制剂观察到的有丝分裂表型的原因的深入了解。
The kinetochore-specific dynein adaptor Spindly is identified as a novel substrate of farnesyltransferase in human cells. Farnesylation is required for Spindly accumulation at kinetochores, and nonfarnesylated Spindly delays chromosome congression, providing new mechanistic insight into the biological effect of farnesyltransferase inhibitors. The clinical interest in farnesyltransferase inhibitors (FTIs) makes it important to understand how these compounds affect cellular processes involving farnesylated proteins. Mitotic abnormalities observed after treatment with FTIs have so far been attributed to defects in the farnesylation of the outer kinetochore proteins CENP-E and CENP-F, which are involved in chromosome congression and spindle assembly checkpoint signaling. Here we identify the cytoplasmic dynein adaptor Spindly as an additional component of the outer kinetochore that is modified by farnesyltransferase (FTase). We show that farnesylation of Spindly is essential for its localization, and thus for the proper localization of dynein and its cofactor dynactin, to prometaphase kinetochores and that Spindly kinetochore recruitment is more severely affected by FTase inhibition than kinetochore recruitment of CENP-E and CENP-F. Molecular replacement experiments show that both Spindly and CENP-E farnesylation are required for efficient chromosome congression. The identification of Spindly as a new mitotic substrate of FTase provides insight into the causes of the mitotic phenotypes observed with FTase inhibitors.