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.

Details

Title
Desumoylase SENP6 maintains osteochondroprogenitor homeostasis by suppressing the p53 pathway
Author
Li, Jianshuang 1 ; Lu, Di 2 ; Dou, Hong 3 ; Liu, Huadie 4 ; Weaver, Kevin 2 ; Wang, Wenjun 5 ; Li, Jiada 6 ; Yeh, Edward TH 3 ; Williams, Bart O 2 ; Zheng, Ling 5 ; Yang, Tao 2   VIAFID ORCID Logo 

1  Center for Cancer and Cell Biology, Van Andel Research Institute, Grand Rapids, MI, USA; Hubei Key Laboratory of Cell Homeostasis, College of Life Sciences, Wuhan University, Wuhan, Hubei, P. R. China 
2  Center for Cancer and Cell Biology, Van Andel Research Institute, Grand Rapids, MI, USA 
3  Center for Precision Medicine, Department of Medicine, University of Missouri, Columbia, MO, USA 
4  Center for Cancer and Cell Biology, Van Andel Research Institute, Grand Rapids, MI, USA; State Key Laboratory of Medical Genetics and School of Life Sciences, Central South University, Changsha, Hunan, P. R. China 
5  Hubei Key Laboratory of Cell Homeostasis, College of Life Sciences, Wuhan University, Wuhan, Hubei, P. R. China 
6  State Key Laboratory of Medical Genetics and School of Life Sciences, Central South University, Changsha, Hunan, P. R. China 
First page
1
Publication year
2018
Publication date
Jan 2018
Publisher
Nature Publishing Group
e-ISSN
20411723
Source type
Scholarly Journal
Language of publication
English
DOI
https://doi.org/10.1038/s41467-017-02413-3
ProQuest document ID
1986196757
Copyright
© 2018. This work is published under http://creativecommons.org/licenses/by/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.