SENP6-Mediated deSUMOylation of Nrf2 Exacerbates Neuronal Oxidative Stress Following Cerebral Ischemia and Reperfusion Injury.

Autor: Xia Q; Department of Anesthesiology and Pain Medicine, Hubei Key Laboratory of Geriatric Anesthesia and Perioperative Brain Health, and Wuhan Clinical Research Center for Geriatric Anesthesia, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China., Que M; Department of Anesthesiology and Pain Medicine, Hubei Key Laboratory of Geriatric Anesthesia and Perioperative Brain Health, and Wuhan Clinical Research Center for Geriatric Anesthesia, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China., Zhan G; Department of Anesthesiology and Pain Medicine, Hubei Key Laboratory of Geriatric Anesthesia and Perioperative Brain Health, and Wuhan Clinical Research Center for Geriatric Anesthesia, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China., Zhang L; Department of Anesthesiology and Pain Medicine, Hubei Key Laboratory of Geriatric Anesthesia and Perioperative Brain Health, and Wuhan Clinical Research Center for Geriatric Anesthesia, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China., Zhang X; Department of Anesthesiology and Pain Medicine, Hubei Key Laboratory of Geriatric Anesthesia and Perioperative Brain Health, and Wuhan Clinical Research Center for Geriatric Anesthesia, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China., Zhao Y; Department of Anesthesiology and Pain Medicine, Hubei Key Laboratory of Geriatric Anesthesia and Perioperative Brain Health, and Wuhan Clinical Research Center for Geriatric Anesthesia, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China., Zhou H; Department of Neurobiology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China., Zheng L; Department of Transfusion, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450000, China., Mao M; Department of Anesthesiology and Perioperative Medicine, Zhengzhou Central Hospital Affiliated to Zhengzhou University, Zhengzhou, 450007, China., Li X; Department of Anesthesiology and Pain Medicine, Hubei Key Laboratory of Geriatric Anesthesia and Perioperative Brain Health, and Wuhan Clinical Research Center for Geriatric Anesthesia, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China.
Jazyk: angličtina
Zdroj: Advanced science (Weinheim, Baden-Wurttemberg, Germany) [Adv Sci (Weinh)] 2024 Dec 24, pp. e2410410. Date of Electronic Publication: 2024 Dec 24.
DOI: 10.1002/advs.202410410
Abstrakt: Oxidative stress is believed to play critical pathophysiological roles in ischemic brain injury, and the nuclear factor erythroid 2-related factor 2 (Nrf2) signaling pathway is recognized as the most crucial endogenous antioxidant stress damage route. Some research have demonstrated that Nrf2 play critical roles in oxidative stress after ischemic stroke, but the underlying mechanism are not fully elucidated. This study reveals that Nrf2 is modified by SUMOylation and identifies Sentrin/SUMO-specific protease 6 (SENP6) as a negative regulator of Nrf2 SUMOylation. Notably, SENP6 binds to and mediates the deSUMOylation of Nrf2, which in turn inhibits antioxidant response by enhancing ubiquitination-dependent degradation of Nrf2, thereby reducing its transcriptional activity, inducing oxidative stress and aggravating neuronal apoptosis after ischemic stroke. Additionally, blocking the interaction between SENP6 and Nrf2 with a cell membrane-permeable peptide (Tat-Nrf2) preserves the SUMOylation of Nrf2, effectively attenuates oxidative stress, and rescues neurological functions in mice subjected to ischemic stroke. Furthermore, no toxicity is observed when high doses Tat-Nrf2 are injected into nonischemic mice. Collectively, this study uncovers a previously unidentified mechanism whereby SUMOylation of Nrf2 regulates oxidative stress and strongly indicates that interventions targeting SENP6 or its interaction with Nrf2 may provide therapeutic benefits for ischemic stroke.
(© 2024 The Author(s). Advanced Science published by Wiley‐VCH GmbH.)
Databáze: MEDLINE
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