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 () and Jun Liu ()
Additional contact information
Li-Kai Chu: Soochow University
Xu Cao: Soochow University
Lin Wan: Soochow University
Qiang Diao: Nanjing University
Yu Zhu: Soochow University
Yu Kan: Soochow University
Li-Li Ye: Soochow University
Yi-Ming Mao: Shanghai Jiao Tong University School of Medicine
Xing-Qiang Dong: Soochow University
Qian-Wei Xiong: Soochow University
Ming-Cui Fu: Soochow University
Ting Zhang: Soochow University
Hui-Ting Zhou: Soochow University
Shi-Zhong Cai: Soochow University
Zhou-Rui Ma: Soochow University
Ssu-Wei Hsu: University of California Davis
Reen Wu: University of California Davis
Ching-Hsien Chen: University of California Davis
Xiang-Ming Yan: Soochow University
Jun Liu: Soochow University

Nature Communications, 2023, vol. 14, issue 1, 1-17

Abstract: 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.

Date: 2023
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DOI: 10.1038/s41467-023-44228-5

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