GSTP1-mediated S-glutathionylation of Pik3r1 is a redox hub that inhibits osteoclastogenesis through regulating autophagic flux

Xiaoxiao Ji; Jianqiao Hong; Weinan Yang; Minjun Yao; Jie Wang; Guangyao Jiang; Yibo Wang; Congsun Li; Jiyan Lin; Haochen Mou; Chaozhong Li; Sihao Li; Yazhou Chen; Minming Shi; Wei Wang; Fei Lu; Haobo Wu; Xiang Zhao; Yiying Qi; Shigui Yan

doi:10.1016/j.redox.2023.102635

GSTP1-mediated S-glutathionylation of Pik3r1 is a redox hub that inhibits osteoclastogenesis through regulating autophagic flux

Redox Biol. 2023 May:61:102635. doi: 10.1016/j.redox.2023.102635. Epub 2023 Feb 27.

Authors

Xiaoxiao Ji¹, Jianqiao Hong², Weinan Yang², Minjun Yao², Jie Wang³, Guangyao Jiang², Yibo Wang², Congsun Li², Jiyan Lin², Haochen Mou², Chaozhong Li⁴, Sihao Li², Yazhou Chen², Minming Shi², Wei Wang², Fei Lu⁵, Haobo Wu⁶, Xiang Zhao⁷, Yiying Qi⁸, Shigui Yan⁹

Affiliations

¹ Department of Orthopedic Surgery, The Fourth Affiliated Hospital, International Institutes of Medicine, Zhejiang University School of Medicine, Yiwu, Zhejiang, PR China; Department of Orthopedic Surgery, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou City, Zhejiang Province, PR China; Orthopedics Research Institute of Zhejiang University, Hangzhou City, Zhejiang Province, PR China; Key Laboratory of Motor System Disease Research and Precision Therapy of Zhejiang Province, Hangzhou City, Zhejiang Province, PR China.
² Department of Orthopedic Surgery, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou City, Zhejiang Province, PR China; Orthopedics Research Institute of Zhejiang University, Hangzhou City, Zhejiang Province, PR China; Key Laboratory of Motor System Disease Research and Precision Therapy of Zhejiang Province, Hangzhou City, Zhejiang Province, PR China.
³ Department of Orthopedic Surgery, The Fourth Affiliated Hospital, International Institutes of Medicine, Zhejiang University School of Medicine, Yiwu, Zhejiang, PR China; Orthopedics Research Institute of Zhejiang University, Hangzhou City, Zhejiang Province, PR China; Key Laboratory of Motor System Disease Research and Precision Therapy of Zhejiang Province, Hangzhou City, Zhejiang Province, PR China.
⁴ College of Computer Science, Sichuan University, Chengdu, PR China.
⁵ Department of Orthopedic Surgery, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou City, Zhejiang Province, PR China.
⁶ Department of Orthopedic Surgery, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou City, Zhejiang Province, PR China; Orthopedics Research Institute of Zhejiang University, Hangzhou City, Zhejiang Province, PR China; Key Laboratory of Motor System Disease Research and Precision Therapy of Zhejiang Province, Hangzhou City, Zhejiang Province, PR China. Electronic address: 2505014@zju.edu.cn.
⁷ Department of Orthopedic Surgery, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou City, Zhejiang Province, PR China; Orthopedics Research Institute of Zhejiang University, Hangzhou City, Zhejiang Province, PR China; Key Laboratory of Motor System Disease Research and Precision Therapy of Zhejiang Province, Hangzhou City, Zhejiang Province, PR China. Electronic address: flyingzhao@zju.edu.cn.
⁸ Department of Orthopedic Surgery, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou City, Zhejiang Province, PR China; Orthopedics Research Institute of Zhejiang University, Hangzhou City, Zhejiang Province, PR China; Key Laboratory of Motor System Disease Research and Precision Therapy of Zhejiang Province, Hangzhou City, Zhejiang Province, PR China. Electronic address: qiyiying@zju.edu.cn.
⁹ Department of Orthopedic Surgery, The Fourth Affiliated Hospital, International Institutes of Medicine, Zhejiang University School of Medicine, Yiwu, Zhejiang, PR China; Department of Orthopedic Surgery, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou City, Zhejiang Province, PR China; Orthopedics Research Institute of Zhejiang University, Hangzhou City, Zhejiang Province, PR China; Key Laboratory of Motor System Disease Research and Precision Therapy of Zhejiang Province, Hangzhou City, Zhejiang Province, PR China. Electronic address: zrjwsj@zju.edu.cn.

Abstract

Glutathione S-transferase P1(GSTP1) is known for its transferase and detoxification activity. Based on disease-phenotype genetic associations, we found that GSTP1 might be associated with bone mineral density through Mendelian randomization analysis. Therefore, this study was performed both in vitro cellular and in vivo mouse model to determine how GSTP1 affects bone homeostasis. In our research, GSTP1 was revealed to upregulate the S-glutathionylation level of Pik3r1 through Cys498 and Cys670, thereby decreasing its phosphorylation, further controlling the alteration of autophagic flux via the Pik3r1-AKT-mTOR axis, and lastly altering osteoclast formation in vitro. In addition, knockdown and overexpression of GSTP1 in vivo also altered bone loss outcomes in the OVX mice model. In general, this study identified a new mechanism by which GSTP1 regulates osteoclastogenesis, and it is evident that the cell fate of osteoclasts is controlled by GSTP1-mediated S-glutathionylation via a redox-autophagy cascade.

Keywords: Autophagic flux; GSTP1; Osteoclastogenesis; Pik3r1/AKT/mTOR; S-glutathionylation.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Autophagy
Glutathione Transferase*
Mice
Osteogenesis*
Oxidation-Reduction
Phosphorylation
Transcription Factors

Substances

Glutathione Transferase
Transcription Factors