Dynamic ubiquitylation of Sox2 regulates proteostasis and governs neural progenitor cell differentiation

Chun-Ping Cui, Yuan Zhang, Chanjuan Wang, Fang Yuan, Hongchang Li, Yuying Yao, Yuhan Chen, Chunnan Li, Wenyi Wei, Cui Hua Liu, Fuchu He, Yan Liu () and Lingqiang Zhang ()
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Chun-Ping Cui: Beijing Institute of Lifeomics
Yuan Zhang: Beijing Institute of Lifeomics
Chanjuan Wang: Beijing Institute of Lifeomics
Fang Yuan: Nanjing Medical University
Hongchang Li: Beijing Institute of Lifeomics
Yuying Yao: Beijing Institute of Lifeomics
Yuhan Chen: Beijing Institute of Lifeomics
Chunnan Li: Beijing Institute of Lifeomics
Wenyi Wei: Harvard Medical School
Cui Hua Liu: Chinese Academy of Sciences
Fuchu He: Beijing Institute of Lifeomics
Yan Liu: Nanjing Medical University
Lingqiang Zhang: Beijing Institute of Lifeomics

Nature Communications, 2018, vol. 9, issue 1, 1-15

Abstract: Abstract Sox2 is a key transcriptional factor for maintaining pluripotency of stem cells. Sox2 deficiency causes neurodegeneration and impairs neurogenesis. Although the transcriptional regulation of Sox2 has been extensively studied, the mechanisms that control Sox2 protein turnover are yet to be clarified. Here we show that the RING-finger ubiquitin ligase complex CUL4ADET1-COP1 and the deubiquitylase OTUD7B govern Sox2 protein stability during neural progenitor cells (NPCs) differentiation. Sox2 expression declines concordantly with OTUD7B and reciprocally with CUL4A and COP1 levels upon NPCs differentiation. COP1, as the substrate receptor, interacts directly with and ubiquitylates Sox2, while OTUD7B removes polyUb conjugates from Sox2 and increases its stability. COP1 knockdown stabilizes Sox2 and prevents differentiation, while OTUD7B knockdown destabilizes Sox2 and induces differentiation. Thus, CUL4ADET1-COP1 and OTUD7B exert opposite roles in regulating Sox2 protein stability at the post-translational level, which represents a critical regulatory mechanism involved in the maintenance and differentiation of NPCs.

Date: 2018
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DOI: 10.1038/s41467-018-07025-z

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