CHIP drives proteasomal degradation of NUR77 to alleviate oxidative stress and intrinsic apoptosis in cisplatin-induced nephropathy.

Autor: Zhang H; Department of Urology, Tianjin Institute of Urology, The Second Hospital of Tianjin Medical University, Tianjin, 300211, China., Deng Z; 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, 410011, China., Wang Y; Department of Cardiology, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China., Zheng X; Department of Urology, The Fifth Affiliated Hospital of Sun Yat-Sen University, Zhuhai, Guangdong, China., Zhou L; Department of Urology, The Second Xiangya Hospital at Central South University, Changsha, Hunan, 410011, China., Yan S; Guangzhou Institute of Pediatrics, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou, Guangdong, China., Wang Y; Department of Urology, The Second Xiangya Hospital at Central South University, Changsha, Hunan, 410011, China., Dai Y; Department of Urology, The Fifth Affiliated Hospital of Sun Yat-Sen University, Zhuhai, Guangdong, China., Kanwar YS; Departments of Pathology & Medicine, Northwestern University, Chicago, IL, USA., Chen F; Department of Urology, The Second Xiangya Hospital at Central South University, Changsha, Hunan, 410011, China. fzc202@126.com., Deng F; Department of Urology, The Second Xiangya Hospital at Central South University, Changsha, Hunan, 410011, China. dengfei1990@csu.edu.cn.; Department of Nephrology, The Second Xiangya Hospital at Central South University, Changsha, Hunan, 410011, China. dengfei1990@csu.edu.cn.
Jazyk: angličtina
Zdroj: Communications biology [Commun Biol] 2024 Oct 26; Vol. 7 (1), pp. 1403. Date of Electronic Publication: 2024 Oct 26.
DOI: 10.1038/s42003-024-07118-0
Abstrakt: Carboxy-terminus of Hsc70-interacting protein (CHIP), an E3 ligase, modulates the stability of its targeted proteins to alleviate various pathological perturbations in various organ systems. Cisplatin is a widely used chemotherapeutic agent, but it is also known for its alarming renal toxicity. The role of CHIP in the pathogenesis of cisplatin-induced acute kidney injury (AKI) has not been adequately investigated. Herein, we demonstrated that CHIP was abundantly expressed in the renal proximal tubular epithelia, and its expression was downregulated in cisplatin-induced AKI. Further investigation revealed that CHIP overexpression or activation alleviated, while its gene disruption promoted, oxidative stress and apoptosis in renal proximal tubular epithelia induced by cisplatin. In terms of mechanism, CHIP interacted with and ubiquitinated NUR77 to promote its degradation, which consequently shielded BCL2 to maintain mitochondrial permeability of renal proximal tubular cells in the presence of cisplatin. Also, we demonstrated that CHIP interacted with NUR77 via its central coiled-coil (CC) domain, a non-canonical interactive pattern. In conclusion, these findings indicated that CHIP ubiquitinated and degraded its substrate NUR77 to attenuate intrinsic apoptosis in cisplatin-treated renal proximal tubular epithelia, thus providing a novel insight for the pathogenesis of cisplatin-induced AKI.
(© 2024. The Author(s).)
Databáze: MEDLINE
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