Department of Gastroenterology, The First Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, Zhejiang, 310003, China.
Institute of Translational Medicine, Zhejiang University School of Medicine, Hangzhou, Zhejiang, 310058, China.
Nat Commun. 2023 Jun 20;14(1):3648. doi: 10.1038/s41467-023-39412-6.
Nuclear factor erythroid 2-related factor 2 (NRF2) is a transcription factor responsible for mounting an anti-oxidation gene expression program to counter oxidative stress. Under unstressed conditions, Kelch-like ECH-associated protein 1 (KEAP1), an adaptor protein for CUL3 E3 ubiquitin ligase, mediates NRF2 ubiquitination and degradation. We show here that the deubiquitinase USP25 directly binds to KEAP1 and prevents KEAP1's own ubiquitination and degradation. In the absence of Usp25 or if the DUB is inhibited, KEAP1 is downregulated and NRF2 is stabilized, allowing the cells to respond to oxidative stress more readily. In acetaminophen (APAP) overdose-induced oxidative liver damage in male mice, the inactivation of Usp25, either genetically or pharmacologically, greatly attenuates liver injury and reduces the mortality rates resulted from lethal doses of APAP.
核因子红细胞 2 相关因子 2（NRF2）是一种转录因子，负责启动抗氧化基因表达程序以对抗氧化应激。在非应激条件下，Kelch 样 ECH 相关蛋白 1（KEAP1）是 CUL3 E3 泛素连接酶的衔接蛋白，介导 NRF2 的泛素化和降解。我们在这里表明，去泛素酶 USP25 直接与 KEAP1 结合，并防止 KEAP1 自身的泛素化和降解。如果没有 Usp25 或抑制 DUB，KEAP1 下调，NRF2 稳定，使细胞更容易应对氧化应激。在雄性小鼠中，对乙酰氨基酚（APAP）过量诱导的氧化肝损伤中，USP25 的失活，无论是遗传失活还是药物抑制，都能大大减轻肝损伤，并降低致命剂量 APAP 导致的死亡率。
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