GSTP1-mediated S-glutathionylation of Pik3r1 is a redox hub that inhibits osteoclastogenesis through regulating autophagic flux
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...
| Main Authors: | , , , , , , , , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Elsevier
2023-05-01
|
| Series: | Redox Biology |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2213231723000368 |
| _version_ | 1811154728837447680 |
|---|---|
| author | 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 |
| author_facet | 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 |
| author_sort | Xiaoxiao Ji |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-04-10T04:21:58Z |
| format | Article |
| id | doaj.art-9ecd62d94a024df6ba10cd2b5d2a7818 |
| institution | Directory Open Access Journal |
| issn | 2213-2317 |
| language | English |
| last_indexed | 2024-04-10T04:21:58Z |
| publishDate | 2023-05-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Redox Biology |
| spelling | doaj.art-9ecd62d94a024df6ba10cd2b5d2a78182023-03-11T04:19:37ZengElsevierRedox Biology2213-23172023-05-0161102635GSTP1-mediated S-glutathionylation of Pik3r1 is a redox hub that inhibits osteoclastogenesis through regulating autophagic fluxXiaoxiao Ji0Jianqiao Hong1Weinan Yang2Minjun Yao3Jie Wang4Guangyao Jiang5Yibo Wang6Congsun Li7Jiyan Lin8Haochen Mou9Chaozhong Li10Sihao Li11Yazhou Chen12Minming Shi13Wei Wang14Fei Lu15Haobo Wu16Xiang Zhao17Yiying Qi18Shigui Yan19Department 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 ChinaDepartment 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 ChinaDepartment 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 ChinaDepartment 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 ChinaDepartment 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 ChinaDepartment 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 ChinaDepartment 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 ChinaDepartment 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 ChinaDepartment 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 ChinaDepartment 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 ChinaCollege of Computer Science, Sichuan University, Chengdu, PR ChinaDepartment 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 ChinaDepartment 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 ChinaDepartment 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 ChinaDepartment 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 ChinaDepartment of Orthopedic Surgery, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou City, Zhejiang Province, PR ChinaDepartment 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; Corresponding author. Department of Orthopedic Surgery, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou City, Zhejiang Province, 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; Corresponding author. Department of Orthopedic Surgery, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou City, Zhejiang Province, 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; Corresponding author. Department of Orthopedic Surgery, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou City, Zhejiang Province, PR China.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; Corresponding author. Department of Orthopedic Surgery, The Fourth Affiliated Hospital, International Institutes of Medicine, Zhejiang University School of Medicine, Yiwu, Zhejiang, PR China.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.http://www.sciencedirect.com/science/article/pii/S2213231723000368GSTP1S-glutathionylationAutophagic fluxOsteoclastogenesisPik3r1/AKT/mTOR |
| spellingShingle | 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 GSTP1-mediated S-glutathionylation of Pik3r1 is a redox hub that inhibits osteoclastogenesis through regulating autophagic flux Redox Biology GSTP1 S-glutathionylation Autophagic flux Osteoclastogenesis Pik3r1/AKT/mTOR |
| title | GSTP1-mediated S-glutathionylation of Pik3r1 is a redox hub that inhibits osteoclastogenesis through regulating autophagic flux |
| title_full | GSTP1-mediated S-glutathionylation of Pik3r1 is a redox hub that inhibits osteoclastogenesis through regulating autophagic flux |
| title_fullStr | GSTP1-mediated S-glutathionylation of Pik3r1 is a redox hub that inhibits osteoclastogenesis through regulating autophagic flux |
| title_full_unstemmed | GSTP1-mediated S-glutathionylation of Pik3r1 is a redox hub that inhibits osteoclastogenesis through regulating autophagic flux |
| title_short | GSTP1-mediated S-glutathionylation of Pik3r1 is a redox hub that inhibits osteoclastogenesis through regulating autophagic flux |
| title_sort | gstp1 mediated s glutathionylation of pik3r1 is a redox hub that inhibits osteoclastogenesis through regulating autophagic flux |
| topic | GSTP1 S-glutathionylation Autophagic flux Osteoclastogenesis Pik3r1/AKT/mTOR |
| url | http://www.sciencedirect.com/science/article/pii/S2213231723000368 |
| work_keys_str_mv | AT xiaoxiaoji gstp1mediatedsglutathionylationofpik3r1isaredoxhubthatinhibitsosteoclastogenesisthroughregulatingautophagicflux AT jianqiaohong gstp1mediatedsglutathionylationofpik3r1isaredoxhubthatinhibitsosteoclastogenesisthroughregulatingautophagicflux AT weinanyang gstp1mediatedsglutathionylationofpik3r1isaredoxhubthatinhibitsosteoclastogenesisthroughregulatingautophagicflux AT minjunyao gstp1mediatedsglutathionylationofpik3r1isaredoxhubthatinhibitsosteoclastogenesisthroughregulatingautophagicflux AT jiewang gstp1mediatedsglutathionylationofpik3r1isaredoxhubthatinhibitsosteoclastogenesisthroughregulatingautophagicflux AT guangyaojiang gstp1mediatedsglutathionylationofpik3r1isaredoxhubthatinhibitsosteoclastogenesisthroughregulatingautophagicflux AT yibowang gstp1mediatedsglutathionylationofpik3r1isaredoxhubthatinhibitsosteoclastogenesisthroughregulatingautophagicflux AT congsunli gstp1mediatedsglutathionylationofpik3r1isaredoxhubthatinhibitsosteoclastogenesisthroughregulatingautophagicflux AT jiyanlin gstp1mediatedsglutathionylationofpik3r1isaredoxhubthatinhibitsosteoclastogenesisthroughregulatingautophagicflux AT haochenmou gstp1mediatedsglutathionylationofpik3r1isaredoxhubthatinhibitsosteoclastogenesisthroughregulatingautophagicflux AT chaozhongli gstp1mediatedsglutathionylationofpik3r1isaredoxhubthatinhibitsosteoclastogenesisthroughregulatingautophagicflux AT sihaoli gstp1mediatedsglutathionylationofpik3r1isaredoxhubthatinhibitsosteoclastogenesisthroughregulatingautophagicflux AT yazhouchen gstp1mediatedsglutathionylationofpik3r1isaredoxhubthatinhibitsosteoclastogenesisthroughregulatingautophagicflux AT minmingshi gstp1mediatedsglutathionylationofpik3r1isaredoxhubthatinhibitsosteoclastogenesisthroughregulatingautophagicflux AT weiwang gstp1mediatedsglutathionylationofpik3r1isaredoxhubthatinhibitsosteoclastogenesisthroughregulatingautophagicflux AT feilu gstp1mediatedsglutathionylationofpik3r1isaredoxhubthatinhibitsosteoclastogenesisthroughregulatingautophagicflux AT haobowu gstp1mediatedsglutathionylationofpik3r1isaredoxhubthatinhibitsosteoclastogenesisthroughregulatingautophagicflux AT xiangzhao gstp1mediatedsglutathionylationofpik3r1isaredoxhubthatinhibitsosteoclastogenesisthroughregulatingautophagicflux AT yiyingqi gstp1mediatedsglutathionylationofpik3r1isaredoxhubthatinhibitsosteoclastogenesisthroughregulatingautophagicflux AT shiguiyan gstp1mediatedsglutathionylationofpik3r1isaredoxhubthatinhibitsosteoclastogenesisthroughregulatingautophagicflux |