A CEP215-HSET complex links centrosomes with spindle poles and drives centrosome clustering in cancer.
A CEP215-HSET complex links centrosomes with spindle poles and drives centrosome clustering in cancer.
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DOI：
10.1038/ncomms11005
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发表时间：
2016-03-18
影响因子：
16.6
通讯作者：
Gergely F
中科院分区：
文献类型：
--
作者：
Chavali PL;Chandrasekaran G;Barr AR;Tátrai P;Taylor C;Papachristou EK;Woods CG;Chavali S;Gergely F
中心体数目畸变是某些发育异常的基础，并可能促进癌症。一个细胞通过中心体复制与分离的耦合来维持正常的中心体数量，这是通过每个中心体与有丝分裂纺锤体极的持续结合来实现的。虽然与小头畸形和原始侏儒症相关的中心体蛋白CEP 215参与了这一过程，但其分子机制仍不清楚。在这里，使用蛋白质组学分析，我们确定负端定向微管马达蛋白HSET作为CEP 215的直接结合伙伴。在脊椎动物细胞中CEP 215的HSET结合结构域的靶向缺失引起中心体脱离并导致中心体处的HSET耗尽，这也是在CEP 215缺陷型患者来源的细胞中观察到的表型。此外，在具有中心体扩增的癌细胞中，CEP 215-HSET复合物促进额外的中心体聚集成假双极纺锤体，从而确保有活力的细胞分裂。因此，CEP 215-HSET复合物稳定中心体-纺锤体极界面可以促进含有额外中心体的癌细胞的存活。 中心体成簇允许具有扩增的中心体的细胞以染色体不稳定性为代价而存活。在这里，Chavali等人表明，中心体组件CEP 215与驱动蛋白马达HSET合作，以维持纺锤体极点连接和聚集中心体。
Numerical centrosome aberrations underlie certain developmental abnormalities and may promote cancer. A cell maintains normal centrosome numbers by coupling centrosome duplication with segregation, which is achieved through sustained association of each centrosome with a mitotic spindle pole. Although the microcephaly- and primordial dwarfism-linked centrosomal protein CEP215 has been implicated in this process, the molecular mechanism responsible remains unclear. Here, using proteomic profiling, we identify the minus end-directed microtubule motor protein HSET as a direct binding partner of CEP215. Targeted deletion of the HSET-binding domain of CEP215 in vertebrate cells causes centrosome detachment and results in HSET depletion at centrosomes, a phenotype also observed in CEP215-deficient patient-derived cells. Moreover, in cancer cells with centrosome amplification, the CEP215–HSET complex promotes the clustering of extra centrosomes into pseudo-bipolar spindles, thereby ensuring viable cell division. Therefore, stabilization of the centrosome–spindle pole interface by the CEP215–HSET complex could promote survival of cancer cells containing supernumerary centrosomes. Centrosome clustering allows survival of cells with amplified centrosomes at the cost of chromosome instability. Here, Chavali et al. show that the centrosome component CEP215 collaborates with the kinesin motor HSET both to maintain spindle poles connections and to cluster centrosomes.