Autophagy of OTUD5 destabilizes GPX4 to confer ferroptosis-dependent kidney injury

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

doi:10.1038/s41467-023-44228-5

Nature Communications (Dec 2023)

Autophagy of OTUD5 destabilizes GPX4 to confer ferroptosis-dependent kidney injury

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

Affiliations

Li-Kai Chu: Pediatric Institute of Soochow University, Children’s Hospital of Soochow University, Soochow University
Xu Cao: Pediatric Institute of Soochow University, Children’s Hospital of Soochow University, Soochow University
Lin Wan: Pediatric Institute of Soochow University, Children’s Hospital of Soochow University, Soochow University
Qiang Diao: Department of Medical Imaging, Jinling Hospital, Affiliated Hospital of Medical School, Nanjing University
Yu Zhu: Pediatric Institute of Soochow University, Children’s Hospital of Soochow University, Soochow University
Yu Kan: Pediatric Institute of Soochow University, Children’s Hospital of Soochow University, Soochow University
Li-Li Ye: Pediatric Institute of Soochow University, Children’s Hospital of Soochow University, Soochow University
Yi-Ming Mao: Department of Thoracic Surgery, Suzhou Kowloon Hospital, Shanghai Jiao Tong University School of Medicine
Xing-Qiang Dong: Pediatric Institute of Soochow University, Children’s Hospital of Soochow University, Soochow University
Qian-Wei Xiong: Pediatric Institute of Soochow University, Children’s Hospital of Soochow University, Soochow University
Ming-Cui Fu: Pediatric Institute of Soochow University, Children’s Hospital of Soochow University, Soochow University
Ting Zhang: Pediatric Institute of Soochow University, Children’s Hospital of Soochow University, Soochow University
Hui-Ting Zhou: Pediatric Institute of Soochow University, Children’s Hospital of Soochow University, Soochow University
Shi-Zhong Cai: Pediatric Institute of Soochow University, Children’s Hospital of Soochow University, Soochow University
Zhou-Rui Ma: Pediatric Institute of Soochow University, Children’s Hospital of Soochow University, Soochow University
Ssu-Wei Hsu: Division of Nephrology, Department of Internal Medicine, University of California Davis
Reen Wu: Division of Pulmonary, Critical Care, and Sleep Medicine, Department of Internal Medicine, University of California Davis
Ching-Hsien Chen: Division of Nephrology, Department of Internal Medicine, University of California Davis
Xiang-Ming Yan: Pediatric Institute of Soochow University, Children’s Hospital of Soochow University, Soochow University
Jun Liu: Pediatric Institute of Soochow University, Children’s Hospital of Soochow University, Soochow University

DOI: https://doi.org/10.1038/s41467-023-44228-5
Journal volume & issue: Vol. 14, no. 1
pp. 1 – 17

Abstract

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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.

Published in Nature Communications

ISSN: 2041-1723 (Online)
Publisher: Nature Portfolio
Country of publisher: United Kingdom
LCC subjects: Science
Website: https://www.nature.com/ncomms/

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