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

Ying Zhao, Shijie Fan, Hong Zhu, Qingqing Zhao, Zimin Fang, Diyun Xu, Wante Lin, Liming Lin, Xiang Hu, Gaojun Wu, Julian Min and Guang Liang ()
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Ying Zhao: the First Affiliated Hospital of 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
Liming Lin: the First Affiliated Hospital of 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

Nature Communications, 2024, vol. 15, issue 1, 1-15

Abstract: 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.

Date: 2024
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DOI: 10.1038/s41467-024-49854-1

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