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

Author

Listed:
  • 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
    University of California Davis)

  • Reen Wu

    (University of California Davis)

  • Ching-Hsien Chen

    (University of California Davis
    University of California Davis)

  • Xiang-Ming Yan

    (Soochow University)

  • Jun Liu

    (Soochow University)

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.

Suggested Citation

  • 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-, 2023. "Autophagy of OTUD5 destabilizes GPX4 to confer ferroptosis-dependent kidney injury," Nature Communications, Nature, vol. 14(1), pages 1-17, December.
    • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-44228-5
    DOI: 10.1038/s41467-023-44228-5
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    References listed on IDEAS

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