EMC3 regulates mesenchymal cell survival via control of the mitotic spindle assembly

Eukaryotic cells transit through the cell cycle to produce two daughter cells. Dysregulation of the cell cycle leads to cell death or tumorigenesis. Herein, we found that a subunit of the Endoplasmic Reticulum (ER) membrane complex, EMC3, is a key regulator of the cell cycle. Conditional deletion of Emc3 in mouse embryonic mesoderm led to reduced size and patterning defects of multiple organs. Emc3 deficiency impaired cell proliferation, causing spindle assembly defects, chromosome mis-segregation, cell cycle arrest at G2/M, and apoptosis. Upon entry into mitosis, mesenchymal cells upregulate EMC3 protein levels and localize EMC3 to the mitotic centrosomes. Further analysis indicated that EMC3 interacts with VCP and Aurora A in mitotic cells. EMC3 works together with VCP to tightly regulate the levels and activity of Aurora A, an essential factor for centrosome function and mitotic spindle assembly: while over-expression of EMC3 or VCP degraded Aurora A, loss of EMC3 or VCP led to increased stability but the reduced activity of Aurora A in mitosis.

真核细胞通过细胞周期过渡，以产生两个子细胞。细胞周期的失调会导致细胞死亡或肿瘤生成。本研究中发现，内质网（Endoplasmic Reticulum，ER）膜复合物的一个亚基，EMC3，是细胞周期的关键调节因子。在鼠胚胎中胚层的Emc3条件性删除导致多个器官的体积减小和模式缺陷。Emc3的缺失损害了细胞增殖，导致纺锤体组装缺陷、染色体非分离、G2/M期细胞周期停滞和细胞凋亡。在进入有丝分裂后，间充质细胞上调EMC3蛋白水平并将EMC3定位于有丝分裂中心体。进一步分析表明，EMC3与VCP和Aurora A在有丝分裂细胞中相互作用。EMC3与VCP协同作用，紧密调控Aurora A的水平与活性，而Aurora A是中心体功能和有丝分裂纺锤体组装的必需因子：EMC3或VCP的过表达会导致Aurora A的降解，而EMC3或VCP的缺失则导致有丝分裂中Aurora A稳定性增加但活性降低。