2. Academic Validation
  3. HSP90β chaperoning SMURF1-mediated LATS proteasomal degradation in the regulation of bone formation

HSP90β chaperoning SMURF1-mediated LATS proteasomal degradation in the regulation of bone formation

  • Cell Signal. 2023 Feb:102:110523. doi: 10.1016/j.cellsig.2022.110523.
Meiyu Qu 1,  Ying Gong 2,  Yuyang Jin 3,  Ruibo Gao 4,  Qiangqiang He 4,  Yana Xu 1,  Tingyu Shen 4,  Liu Mei 5,  Chengyun Xu 4,  Musaddique Hussain 4,  Muhammad Qasim Barkat 4,  Ximei Wu 6
Affiliations

Affiliations

  • 1 Department of Pharmacology, Zhejiang University School of Medicine, Hangzhou 310058, China,; Department of Orthopaedics, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou 310016, China.
  • 2 Department of Pharmacy, Affiliated Hangzhou First People's Hospital, Zhejiang University School of Medicine, Hangzhou 310006, China. Electronic address: 412254579@qq.com.
  • 3 Shanghai Luyi Cell Biotech Co., Ltd, Jiading District, Shanghai 201821, China.
  • 4 Department of Pharmacology, Zhejiang University School of Medicine, Hangzhou 310058, China.
  • 5 Department of Biochemistry and Biophysics, University of North Carolina-Chapel Hill, Chapel Hill, NC 27599, USA.
  • 6 Department of Pharmacology, Zhejiang University School of Medicine, Hangzhou 310058, China,; Department of Orthopaedics, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou 310016, China. Electronic address: xiwu@zju.edu.cn.
PMID: 36379376 DOI: 10.1016/j.cellsig.2022.110523
Abstract

Heat shock protein 90 (HSP90) molecular chaperone is responsible for the stabilization and biological activity of a diverse set of client proteins. We have previously demonstrated that inhibition of HSP90 by 17-Demethoxy-17-allyaminogeldanmycin (17-AAG) not only reverses the glucocorticoid-induced bone loss but also enhances the basal level of bone mass in mice. Here, we investigate the potential mechanism underlying HSP90-associated osteoblast differentiation and bone formation. Knockdown of HSP90β but not HSP90α or inhibition of HSP90 by 17-AAG or NVP-BEP800 negates the protein levels of large tumor suppressor (LATS), the core kinases of Hippo signaling, resulting in the inactivation of LATS and activation of Yes-associated protein (YAP) and transcriptional coactivator with PDZ-binding motif (TAZ), in the enhancement of osteoblastic differentiation. In contrast, genetic ablation of Lats1 in mesenchymal stem cells is sufficient to abolish the HSP90 inhibition-induced osteoblastic differentiation and bone formation. Mechanistically, HSP90β but not HSP90α chaperones and prevents the SMAD specific E3 ubiquitin protein Ligase 1 (SMURF1)-mediated and ubiquitination-dependent LATS protein proteasomal degradation, whereas 17-AAG abolishes these effects of HSP90β. Thus, these results uncover the HSP90β chaperoning SMURF1-mediated LATS protein proteasomal degradation and the subsequent YAP/TAZ activation as a hitherto uncharacterized mechanism controlling osteoblastic differentiation and bone formation.

Keywords

17-AAG; HSP90β; LATS; Osteoblast; SMURF1.

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