EMC3 regulates mesenchymal cell survival via control of the mitotic spindle assembly
Xiaofang Tang,
Wei Wei,
John M. Snowball,
Ernesto S. Nakayasu,
Sheila M. Bell,
Charles Ansong,
Xinhua Lin,
Jeffrey A. Whitsett
Affiliations
Xiaofang Tang
Perinatal Institute, Divisions of Neonatology, Perinatal and Pulmonary Biology, Cincinnati Children’s Hospital Medical Center, 3333 Burnet Avenue, MLC 7029, Cincinnati, OH 45229, USA; Greater Bay Area Institute of Precision Medicine (Guangzhou), Fudan University, 2nd Nanjiang Rd, Nansha District, Guangzhou 511458, China
Wei Wei
State Key Laboratory of Genetic Engineering, School of Life Sciences, Zhongshan Hospital, Fudan University, No. 2005 Songhu Rd, Shanghai 200438, China
John M. Snowball
Perinatal Institute, Divisions of Neonatology, Perinatal and Pulmonary Biology, Cincinnati Children’s Hospital Medical Center, 3333 Burnet Avenue, MLC 7029, Cincinnati, OH 45229, USA
Ernesto S. Nakayasu
Biological Sciences Division, Pacific Northwest National Laboratory, 902 Battelle Blvd, Richland, WA 99354, USA
Sheila M. Bell
Perinatal Institute, Divisions of Neonatology, Perinatal and Pulmonary Biology, Cincinnati Children’s Hospital Medical Center, 3333 Burnet Avenue, MLC 7029, Cincinnati, OH 45229, USA
Charles Ansong
Biological Sciences Division, Pacific Northwest National Laboratory, 902 Battelle Blvd, Richland, WA 99354, USA
Xinhua Lin
Greater Bay Area Institute of Precision Medicine (Guangzhou), Fudan University, 2nd Nanjiang Rd, Nansha District, Guangzhou 511458, China; State Key Laboratory of Genetic Engineering, School of Life Sciences, Zhongshan Hospital, Fudan University, No. 2005 Songhu Rd, Shanghai 200438, China; Corresponding author
Jeffrey A. Whitsett
Perinatal Institute, Divisions of Neonatology, Perinatal and Pulmonary Biology, Cincinnati Children’s Hospital Medical Center, 3333 Burnet Avenue, MLC 7029, Cincinnati, OH 45229, USA; Corresponding author
Summary: 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 a subunit of the ER membrane complex, EMC3, as a key regulator of 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 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 overexpression of EMC3 or VCP degraded Aurora A, their loss led to increased Aurora A stability but reduced Aurora A phosphorylation in mitosis.
