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

Authors :
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
Source :
Nature Communications, Vol 14, Iss 1, Pp 1-17 (2023)
Publication Year :
2023
Publisher :
Nature Portfolio, 2023.

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.

Subjects

Subjects :
Science

Details

Language :
English
ISSN :
20411723
Volume :
14
Issue :
1
Database :
Directory of Open Access Journals
Journal :
Nature Communications
Publication Type :
Academic Journal
Accession number :
edsdoj.7aaff6ff3e147cc84fd1059eeb1f2ae
Document Type :
article
Full Text :
https://doi.org/10.1038/s41467-023-44228-5