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.