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Podocyte OTUD5 alleviates diabetic kidney disease through deubiquitinating TAK1 and reducing podocyte inflammation and injury

Author

Listed:
  • Ying Zhao

    (the First Affiliated Hospital of Wenzhou Medical University
    Wenzhou Medical University)

  • Shijie Fan

    (Wenzhou Medical University)

  • Hong Zhu

    (the First Affiliated Hospital of Wenzhou Medical University)

  • Qingqing Zhao

    (Wenzhou Medical University)

  • Zimin Fang

    (the First Affiliated Hospital of Wenzhou Medical University)

  • Diyun Xu

    (the First Affiliated Hospital of Wenzhou Medical University)

  • Wante Lin

    (Wenzhou Medical University
    the First Affiliated Hospital of Wenzhou Medical University)

  • Liming Lin

    (the First Affiliated Hospital of Wenzhou Medical University
    Wenzhou Medical University)

  • Xiang Hu

    (the First Affiliated Hospital of Wenzhou Medical University)

  • Gaojun Wu

    (the First Affiliated Hospital of Wenzhou Medical University)

  • Julian Min

    (Wenzhou Medical University)

  • Guang Liang

    (the First Affiliated Hospital of Wenzhou Medical University
    Wenzhou Medical University
    Hangzhou Medical College)

Abstract

Recent studies have shown the crucial role of podocyte injury in the development of diabetic kidney disease (DKD). Deubiquitinating modification of proteins is widely involved in the occurrence and development of diseases. Here, we explore the role and regulating mechanism of a deubiquitinating enzyme, OTUD5, in podocyte injury and DKD. RNA-seq analysis indicates a significantly decreased expression of OTUD5 in HG/PA-stimulated podocytes. Podocyte-specific Otud5 knockout exacerbates podocyte injury and DKD in both type 1 and type 2 diabetic mice. Furthermore, AVV9-mediated OTUD5 overexpression in podocytes shows a therapeutic effect against DKD. Mass spectrometry and co-immunoprecipitation experiments reveal an inflammation-regulating protein, TAK1, as the substrate of OTUD5 in podocytes. Mechanistically, OTUD5 deubiquitinates K63-linked TAK1 at the K158 site through its active site C224, which subsequently prevents the phosphorylation of TAK1 and reduces downstream inflammatory responses in podocytes. Our findings show an OTUD5-TAK1 axis in podocyte inflammation and injury and highlight the potential of OTUD5 as a promising therapeutic target for DKD.

Suggested Citation

  • Ying Zhao & Shijie Fan & Hong Zhu & Qingqing Zhao & Zimin Fang & Diyun Xu & Wante Lin & Liming Lin & Xiang Hu & Gaojun Wu & Julian Min & Guang Liang, 2024. "Podocyte OTUD5 alleviates diabetic kidney disease through deubiquitinating TAK1 and reducing podocyte inflammation and injury," Nature Communications, Nature, vol. 15(1), pages 1-15, December.
    • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-49854-1
    DOI: 10.1038/s41467-024-49854-1
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    References listed on IDEAS

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    1. 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.
    2. Jun Ninomiya-Tsuji & Kazuya Kishimoto & Atsushi Hiyama & Jun-ichiro Inoue & Zhaodan Cao & Kunihiro Matsumoto, 1999. "The kinase TAK1 can activate the NIK-IκB as well as the MAP kinase cascade in the IL-1 signalling pathway," Nature, Nature, vol. 398(6724), pages 252-256, March.
    3. Fangzhou Li & Qianqian Sun & Kun Liu & Ling Zhang & Ning Lin & Kaiqiang You & Mingwei Liu & Ning Kon & Feng Tian & Zebin Mao & Tingting Li & Tanjun Tong & Jun Qin & Wei Gu & Dawei Li & Wenhui Zhao, 2020. "OTUD5 cooperates with TRIM25 in transcriptional regulation and tumor progression via deubiquitination activity," Nature Communications, Nature, vol. 11(1), pages 1-16, December.
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