Autophagy of OTUD5 destabilizes GPX4 to confer ferroptosis-dependent kidney injury
Abstract Ferroptosis is an iron-dependent programmed cell death associated with severe kidney diseases, linked to decreased glutathione peroxidase 4 (GPX4). However, the spatial distribution of renal GPX4-mediated ferroptosis and the molecular events causing GPX4 reduction during ischemia-reperfusio...
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| Format: | Article |
| Language: | English |
| Published: |
Nature Portfolio
2023-12-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-023-44228-5 |
| _version_ | 1797376940939673600 |
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| author | Li-Kai Chu Xu Cao Lin Wan Qiang Diao Yu Zhu Yu Kan Li-Li Ye Yi-Ming Mao Xing-Qiang Dong Qian-Wei Xiong Ming-Cui Fu Ting Zhang Hui-Ting Zhou Shi-Zhong Cai Zhou-Rui Ma Ssu-Wei Hsu Reen Wu Ching-Hsien Chen Xiang-Ming Yan Jun Liu |
| author_facet | Li-Kai Chu Xu Cao Lin Wan Qiang Diao Yu Zhu Yu Kan Li-Li Ye Yi-Ming Mao Xing-Qiang Dong Qian-Wei Xiong Ming-Cui Fu Ting Zhang Hui-Ting Zhou Shi-Zhong Cai Zhou-Rui Ma Ssu-Wei Hsu Reen Wu Ching-Hsien Chen Xiang-Ming Yan Jun Liu |
| author_sort | Li-Kai Chu |
| collection | DOAJ |
| description | Abstract Ferroptosis is an iron-dependent programmed cell death associated with severe kidney diseases, linked to decreased glutathione peroxidase 4 (GPX4). However, the spatial distribution of renal GPX4-mediated ferroptosis and the molecular events causing GPX4 reduction during ischemia-reperfusion (I/R) remain largely unknown. Using spatial transcriptomics, we identify that GPX4 is situated at the interface of the inner cortex and outer medulla, a hyperactive ferroptosis site post-I/R injury. We further discover OTU deubiquitinase 5 (OTUD5) as a GPX4-binding protein that confers ferroptosis resistance by stabilizing GPX4. During I/R, ferroptosis is induced by mTORC1-mediated autophagy, causing OTUD5 degradation and subsequent GPX4 decay. Functionally, OTUD5 deletion intensifies renal tubular cell ferroptosis and exacerbates acute kidney injury, while AAV-mediated OTUD5 delivery mitigates ferroptosis and promotes renal function recovery from I/R injury. Overall, this study highlights a new autophagy-dependent ferroptosis module: hypoxia/ischemia-induced OTUD5 autophagy triggers GPX4 degradation, offering a potential therapeutic avenue for I/R-related kidney diseases. |
| first_indexed | 2024-03-08T19:45:52Z |
| format | Article |
| id | doaj.art-d7aaff6ff3e147cc84fd1059eeb1f2ae |
| institution | Directory Open Access Journal |
| issn | 2041-1723 |
| language | English |
| last_indexed | 2024-03-08T19:45:52Z |
| publishDate | 2023-12-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj.art-d7aaff6ff3e147cc84fd1059eeb1f2ae2023-12-24T12:24:19ZengNature PortfolioNature Communications2041-17232023-12-0114111710.1038/s41467-023-44228-5Autophagy of OTUD5 destabilizes GPX4 to confer ferroptosis-dependent kidney injuryLi-Kai Chu0Xu Cao1Lin Wan2Qiang Diao3Yu Zhu4Yu Kan5Li-Li Ye6Yi-Ming Mao7Xing-Qiang Dong8Qian-Wei Xiong9Ming-Cui Fu10Ting Zhang11Hui-Ting Zhou12Shi-Zhong Cai13Zhou-Rui Ma14Ssu-Wei Hsu15Reen Wu16Ching-Hsien Chen17Xiang-Ming Yan18Jun Liu19Pediatric Institute of Soochow University, Children’s Hospital of Soochow University, Soochow UniversityPediatric Institute of Soochow University, Children’s Hospital of Soochow University, Soochow UniversityPediatric Institute of Soochow University, Children’s Hospital of Soochow University, Soochow UniversityDepartment of Medical Imaging, Jinling Hospital, Affiliated Hospital of Medical School, Nanjing UniversityPediatric Institute of Soochow University, Children’s Hospital of Soochow University, Soochow UniversityPediatric Institute of Soochow University, Children’s Hospital of Soochow University, Soochow UniversityPediatric Institute of Soochow University, Children’s Hospital of Soochow University, Soochow UniversityDepartment of Thoracic Surgery, Suzhou Kowloon Hospital, Shanghai Jiao Tong University School of MedicinePediatric Institute of Soochow University, Children’s Hospital of Soochow University, Soochow UniversityPediatric Institute of Soochow University, Children’s Hospital of Soochow University, Soochow UniversityPediatric Institute of Soochow University, Children’s Hospital of Soochow University, Soochow UniversityPediatric Institute of Soochow University, Children’s Hospital of Soochow University, Soochow UniversityPediatric Institute of Soochow University, Children’s Hospital of Soochow University, Soochow UniversityPediatric Institute of Soochow University, Children’s Hospital of Soochow University, Soochow UniversityPediatric Institute of Soochow University, Children’s Hospital of Soochow University, Soochow UniversityDivision of Nephrology, Department of Internal Medicine, University of California DavisDivision of Pulmonary, Critical Care, and Sleep Medicine, Department of Internal Medicine, University of California DavisDivision of Nephrology, Department of Internal Medicine, University of California DavisPediatric Institute of Soochow University, Children’s Hospital of Soochow University, Soochow UniversityPediatric Institute of Soochow University, Children’s Hospital of Soochow University, Soochow UniversityAbstract Ferroptosis is an iron-dependent programmed cell death associated with severe kidney diseases, linked to decreased glutathione peroxidase 4 (GPX4). However, the spatial distribution of renal GPX4-mediated ferroptosis and the molecular events causing GPX4 reduction during ischemia-reperfusion (I/R) remain largely unknown. Using spatial transcriptomics, we identify that GPX4 is situated at the interface of the inner cortex and outer medulla, a hyperactive ferroptosis site post-I/R injury. We further discover OTU deubiquitinase 5 (OTUD5) as a GPX4-binding protein that confers ferroptosis resistance by stabilizing GPX4. During I/R, ferroptosis is induced by mTORC1-mediated autophagy, causing OTUD5 degradation and subsequent GPX4 decay. Functionally, OTUD5 deletion intensifies renal tubular cell ferroptosis and exacerbates acute kidney injury, while AAV-mediated OTUD5 delivery mitigates ferroptosis and promotes renal function recovery from I/R injury. Overall, this study highlights a new autophagy-dependent ferroptosis module: hypoxia/ischemia-induced OTUD5 autophagy triggers GPX4 degradation, offering a potential therapeutic avenue for I/R-related kidney diseases.https://doi.org/10.1038/s41467-023-44228-5 |
| spellingShingle | Li-Kai Chu Xu Cao Lin Wan Qiang Diao Yu Zhu Yu Kan Li-Li Ye Yi-Ming Mao Xing-Qiang Dong Qian-Wei Xiong Ming-Cui Fu Ting Zhang Hui-Ting Zhou Shi-Zhong Cai Zhou-Rui Ma Ssu-Wei Hsu Reen Wu Ching-Hsien Chen Xiang-Ming Yan Jun Liu Autophagy of OTUD5 destabilizes GPX4 to confer ferroptosis-dependent kidney injury Nature Communications |
| title | Autophagy of OTUD5 destabilizes GPX4 to confer ferroptosis-dependent kidney injury |
| title_full | Autophagy of OTUD5 destabilizes GPX4 to confer ferroptosis-dependent kidney injury |
| title_fullStr | Autophagy of OTUD5 destabilizes GPX4 to confer ferroptosis-dependent kidney injury |
| title_full_unstemmed | Autophagy of OTUD5 destabilizes GPX4 to confer ferroptosis-dependent kidney injury |
| title_short | Autophagy of OTUD5 destabilizes GPX4 to confer ferroptosis-dependent kidney injury |
| title_sort | autophagy of otud5 destabilizes gpx4 to confer ferroptosis dependent kidney injury |
| url | https://doi.org/10.1038/s41467-023-44228-5 |
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