WWP2 deletion aggravates acute kidney injury by targeting CDC20/autophagy axis

作者：Ran You, Yanwei Li, Yuteng Jiang, Dandan Hu, Menglei Gu, Wei Zhou, S. H. Zhang, Mi Bai, Yunwen Yang, Yue Zhang, Songming Huang, Zhanjun Jia, Aihua Zhang · 发表于：Journal of Advanced Research · 年份：2024 · DOI：10.1016/j.jare.2024.06.015 · 被引用次数：11 · 研究领域：Autophagy in Disease and Therapy、Acute Kidney Injury Research、Ubiquitin and proteasome pathways

INTRODUCTION: Acute kidney injury (AKI) is associated with high morbidity and mortality rates. The molecular mechanisms underlying AKI are currently being extensively investigated. WWP2 is an E3 ligase that regulates cell proliferation and differentiation. Whether WWP2 plays a regulatory role in AKI remains to be elucidated. OBJECTIVES: We aimed to investigate the implication of WWP2 in AKI and its underlying mechanism in the present study. METHODS: We utilized renal tissues from patients with AKI and established AKI models in global or tubule-specific knockout (cKO) mice strains to study WWP2's implication in AKI. We also systemically analyzed ubiquitylation omics and proteomics to decipher the underlying mechanism. RESULTS: In the present study, we found that WWP2 expression significantly increased in the tubules of kidneys with AKI. Global or tubule-specific knockout of WWP2 significantly aggravated renal dysfunction and tubular injury in AKI kidneys, whereas WWP2 overexpression significantly protected tubular epithelial cells against cisplatin. WWP2 deficiency profoundly affected autophagy in AKI kidneys. Further analysis with ubiquitylation omics, quantitative proteomics and experimental validation suggested that WWP2 mediated poly-ubiquitylation of CDC20, a negative regulator of autophagy. CDC20 was significantly decreased in AKI kidneys, and selective inhibiting CDC20 with apcin profoundly alleviated renal dysfunction and tubular injury in the cisplatin model with or w...