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Int J Biol Sci 2023; 19(8):2319-2332. doi:10.7150/ijbs.82152 This issue Cite

Research Paper

The deubiquitinase UCHL1 negatively controls osteoclastogenesis by regulating TAZ/NFATC1 signalling

Zhenhua Feng1,2*, Siyue Tao1,2*, Zhaobo Huang1,2*, Bingjie Zheng1,2, Xiangxi Kong1,2, Yufeng Xiang1,2, Qibin Zhang1,2, Haixin Song1,2, Zhikun Xu1,2, Xiaoan Wei1,2, Fengdong Zhao✉, Jian Chen✉

1. Department of Orthopaedic Surgery, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China
2. Key Laboratory of Musculoskeletal System Degeneration and Regeneration Translational Research of Zhejiang Province, Hangzhou, China
* These authors contributed equally

✉ Corresponding authors: Jian Chen (chenjian-bioedu.cn) and Fengdong Zhao (zhaofengdongedu.cn)

Citation:
Feng Z, Tao S, Huang Z, Zheng B, Kong X, Xiang Y, Zhang Q, Song H, Xu Z, Wei X, Zhao F, Chen J. The deubiquitinase UCHL1 negatively controls osteoclastogenesis by regulating TAZ/NFATC1 signalling. Int J Biol Sci 2023; 19(8):2319-2332. doi:10.7150/ijbs.82152. https://www.ijbs.com/v19p2319.htm
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Abstract

Graphic abstract

The ubiquitin‒proteasome system (UPS) plays a key role in maintaining protein homeostasis and bone remodelling. However, the role of deubiquitinating enzymes (DUBs) in bone resorption is still not well defined. Here, we identified the deubiquitinase ubiquitin C-terminal hydrolase 1 (UCHL1) as a negative regulator of osteoclastogenesis by using the GEO database, proteomic analysis, and RNAi. Osteoclast-specific UCHL1 conditional knockout mice exhibited a severe osteoporosis phenotype in an ovariectomized model. Mechanistically, UCHL1 deubiquitinated and stabilized the transcriptional coactivator with PDZ-binding motif (TAZ) at the K46 residue, thereby inhibiting osteoclastogenesis. The TAZ protein underwent K48-linked polyubiquitination, which was degraded by UCHL1. As a substrate of UCHL1, TAZ regulates NFATC1 through a nontranscriptional coactivator function by competing with calcineurin A (CNA) for binding to NFATC1, which inhibits NFATC1 dephosphorylation and nuclear transport to impede osteoclastogenesis. Moreover, overexpression of UCHL1 locally alleviated acute and chronic bone loss. These findings suggest that activating UCHL1 may serve as a novel therapeutic approach targeting bone loss in various bone pathological states.

Keywords: UCHL1, TAZ, Osteoclast, NFATC1, osteoporosis

Citation styles

APA
Feng, Z., Tao, S., Huang, Z., Zheng, B., Kong, X., Xiang, Y., Zhang, Q., Song, H., Xu, Z., Wei, X., Zhao, F., Chen, J. (2023). The deubiquitinase UCHL1 negatively controls osteoclastogenesis by regulating TAZ/NFATC1 signalling. International Journal of Biological Sciences, 19(8), 2319-2332. https://doi.org/10.7150/ijbs.82152.

ACS
Feng, Z.; Tao, S.; Huang, Z.; Zheng, B.; Kong, X.; Xiang, Y.; Zhang, Q.; Song, H.; Xu, Z.; Wei, X.; Zhao, F.; Chen, J. The deubiquitinase UCHL1 negatively controls osteoclastogenesis by regulating TAZ/NFATC1 signalling. Int. J. Biol. Sci. 2023, 19 (8), 2319-2332. DOI: 10.7150/ijbs.82152.

NLM
Feng Z, Tao S, Huang Z, Zheng B, Kong X, Xiang Y, Zhang Q, Song H, Xu Z, Wei X, Zhao F, Chen J. The deubiquitinase UCHL1 negatively controls osteoclastogenesis by regulating TAZ/NFATC1 signalling. Int J Biol Sci 2023; 19(8):2319-2332. doi:10.7150/ijbs.82152. https://www.ijbs.com/v19p2319.htm

CSE
Feng Z, Tao S, Huang Z, Zheng B, Kong X, Xiang Y, Zhang Q, Song H, Xu Z, Wei X, Zhao F, Chen J. 2023. The deubiquitinase UCHL1 negatively controls osteoclastogenesis by regulating TAZ/NFATC1 signalling. Int J Biol Sci. 19(8):2319-2332.

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