Hori Akiko, Peddie Christopher J, Collinson Lucy M, Toda Takashi
The Francis Crick Institute, Lincoln's Inn Fields Laboratory, London WC2A 3LY, United Kingdom.
The Francis Crick Institute, Lincoln's Inn Fields Laboratory, London WC2A 3LY, United Kingdom
Mol Biol Cell. 2015 Jun 1;26(11):2005-19. doi: 10.1091/mbc.E14-11-1561. Epub 2015 Apr 1.
Centriolar satellites are numerous electron-dense granules dispersed around the centrosome. Mutations in their components are linked to various human diseases, but their molecular roles remain elusive. In particular, the significance of spatial communication between centriolar satellites and the centrosome is unknown. hMsd1/SSX2IP localizes to both the centrosome and centriolar satellites and is required for tethering microtubules to the centrosome. Here we show that hMsd1/SSX2IP-mediated microtubule anchoring is essential for proper centriole assembly and duplication. On hMsd1/SSX2IP knockdown, the centriolar satellites become stuck at the microtubule minus end near the centrosome. Intriguingly, these satellites contain many proteins that normally localize to the centrosome. Of importance, microtubule structures, albeit not being anchored properly, are still required for the emergence of abnormal satellites, as complete microtubule depolymerization results in the disappearance of these aggregates from the vicinity of the centrosome. We highlighted, using superresolution and electron microscopy, that under these conditions, centriole structures are faulty. Remarkably, these cells are insensitive to Plk4 overproduction-induced ectopic centriole formation, yet they accelerate centrosome reduplication upon hydroxyurea arrest. Finally, the appearance of satellite aggregates is cancer cell specific. Together our findings provide novel insights into the mechanism of centriole assembly and microtubule anchoring.
中心粒卫星是分散在中心体周围的众多电子致密颗粒。其组成成分的突变与多种人类疾病相关，但其分子作用仍不清楚。特别是，中心粒卫星与中心体之间空间通讯的意义尚不清楚。hMsd1/SSX2IP定位于中心体和中心粒卫星，是将微管拴系到中心体所必需的。在此我们表明，hMsd1/SSX2IP介导的微管锚定对于中心粒的正确组装和复制至关重要。在敲低hMsd1/SSX2IP后，中心粒卫星会卡在中心体附近的微管负端。有趣的是，这些卫星包含许多通常定位于中心体的蛋白质。重要的是，微管结构虽然没有正确锚定，但异常卫星的出现仍然需要微管结构，因为完全的微管解聚会导致这些聚集体从中心体附近消失。我们使用超分辨率和电子显微镜强调，在这些条件下，中心粒结构存在缺陷。值得注意的是，这些细胞对Plk4过量表达诱导的异位中心粒形成不敏感，但在羟基脲阻滞时它们会加速中心体的再复制。最后，卫星聚集体的出现具有癌细胞特异性。我们的研究结果共同为中心粒组装和微管锚定机制提供了新的见解。
