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循环产生两个子细胞。细胞周期失调会引发细胞死亡或肿瘤发生。本研究发现，内质网（Endoplasmic Reticulum, ER）膜复合物的亚基EMC3是细胞周期的关键调控因子。在小鼠胚胎中胚层内条件性敲除Emc3，会导致多个器官体积减小并出现模式构建缺陷。Emc3缺陷会损害细胞增殖，引发纺锤体组装缺陷、染色体分离错误、G2/M期细胞周期阻滞以及细胞凋亡。进入有丝分裂阶段后，间充质细胞会上调EMC3的蛋白表达水平，并将EMC3定位至有丝分裂中心体。进一步分析显示，在有丝分裂细胞中，EMC3可与VCP及极光激酶A（Aurora A）相互作用。EMC3与VCP协同作用，严格调控极光激酶A的表达水平与活性——极光激酶A是中心体功能及有丝分裂纺锤体组装的必需因子：当EMC3或VCP过表达时会降解极光激酶A；而EMC3或VCP缺失则会导致有丝分裂阶段极光激酶A的稳定性升高，但活性降低。