WBP2 restrains the lysosomal degradation of GPX4 to inhibit ferroptosis in cisplatin-induced acute kidney injury
Zebin Deng,
Yilong Wang,
Jiachen Liu,
Hao Zhang,
Lizhi Zhou,
Hao Zhao,
Yachun Han,
Shu Yan,
Zheng Dong,
Yinhuai Wang,
Yingbo Dai,
Fei Deng
Affiliations
Zebin Deng
Department of Urology, The Second Xiangya Hospital at Central South University, Changsha, Hunan, 410011, China
Yilong Wang
Department of Cardiology, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China
Jiachen Liu
The Center of Systems Biology and Data Science, School of Basic Medical Science, Central South University, Changsha, Hunan, China
Hao Zhang
Department of Urology, The Second Xiangya Hospital at Central South University, Changsha, Hunan, 410011, China
Lizhi Zhou
Department of Urology, The Second Xiangya Hospital at Central South University, Changsha, Hunan, 410011, China
Hao Zhao
Department of Nephrology, The Second Xiangya Hospital at Central South University, Changsha, Hunan, China
Yachun Han
Department of Nephrology, The Second Xiangya Hospital at Central South University, Changsha, Hunan, China
Shu Yan
Guangzhou Institute of Pediatrics, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou, Guangdong, China
Zheng Dong
Department of Nephrology, The Second Xiangya Hospital at Central South University, Changsha, Hunan, China; Department of Cellular Biology and Anatomy, Medical College of Georgia at Augusta University, Augusta, GA, USA
Yinhuai Wang
Department of Urology, The Second Xiangya Hospital at Central South University, Changsha, Hunan, 410011, China
Yingbo Dai
Department of Urology, The Fifth Affiliated Hospital of Sun Yat-Sen University, Zhuhai, Guangdong, China
Fei Deng
Department of Urology, The Second Xiangya Hospital at Central South University, Changsha, Hunan, 410011, China; Department of Nephrology, The Second Xiangya Hospital at Central South University, Changsha, Hunan, China; Corresponding author. Department of Urology & Nephrology, the Second Xiangya Hospital, Central South University, 139 Middle Renmin Road, Changsha, Hunan, 410011, China.
Cisplatin is one of the major causes of acute kidney injury (AKI) in clinical practice, and ferroptosis is an essential form of cell death in cisplatin-induced AKI (CP-AKI). WW domain binding protein-2 (WBP2), a molecular chaperon, is involved in the progression of various malignancies, but its role in renal injuries has not been investigated. Our present study employed bioinformatics analysis to identify WBP2 as a potential modulator of AKI and ferroptosis. Preliminary laboratory investigations showed that WBP2, highly expressed in renal proximal tubular cells, was downregulated in CP-AKI. Further studies demonstrated that WBP2 decelerated ferroptosis to alleviate CP-AKI. Mechanistically, WBP2 interacted with glutathione peroxidase 4 (GPX4, a key detoxicating enzyme for ferroptosis) via its PPXY1 motif to inhibit ferroptosis. Furthermore, the in-depth investigations revealed that WBP2 competed with heat shock cognate protein 70 (HSC70) for the binding with the KEFRQ-like motifs of GPX4, leading to the deceleration of chaperon-mediated autophagy of GPX4. All in all, this study indicated the beneficial effect of WBP2 in CP-AKI and its relevance with ferroptosis, thus providing a novel insight into the modulation of ferroptosis in cisplatin-related nephropathy.
