Desumoylase SENP6 maintains osteochondroprogenitor homeostasis by suppressing the p53 pathway

Jianshuang Li, Di Lu, Hong Dou, Huadie Liu, Kevin Weaver, Wenjun Wang, Jiada Li, Edward T.H. Yeh, Bart O. Williams, Ling Zheng () and Tao Yang ()
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Jianshuang Li: Van Andel Research Institute
Di Lu: Van Andel Research Institute
Hong Dou: University of Missouri
Huadie Liu: Van Andel Research Institute
Kevin Weaver: Van Andel Research Institute
Wenjun Wang: Wuhan University
Jiada Li: Central South University
Edward T.H. Yeh: University of Missouri
Bart O. Williams: Van Andel Research Institute
Ling Zheng: Wuhan University
Tao Yang: Van Andel Research Institute

Nature Communications, 2018, vol. 9, issue 1, 1-14

Abstract: Abstract The development, growth, and renewal of skeletal tissues rely on the function of osteochondroprogenitors (OCPs). Protein sumoylation/desumoylation has emerged as a pivotal mechanism for stem cell/progenitor homeostasis, and excessive sumoylation has been associated with cell senescence and tissue aging, but its role in regulating OCP function is unclear. Here we show that postnatal loss of the desumoylase SUMO1/sentrin-specific peptidase 6 (SENP6) causes premature aging. OCP-specific SENP6 knockout mice exhibit smaller skeletons, with elevated apoptosis and cell senescence in OCPs and chondrocytes. In Senp6 ‒/‒ cells, the two most significantly elevated pathways are p53 signaling and senescence-associated secreted phenotypes (SASP), and Trp53 loss partially rescues the skeletal and cellular phenotypes caused by Senp6 loss. Furthermore, SENP6 interacts with, desumoylates, and stabilizes TRIM28, suppressing p53 activity. Our data reveals a crucial role of the SENP6–p53 axis in maintaining OCP homeostasis during skeletal development.

Date: 2018
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DOI: 10.1038/s41467-017-02413-3

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