Journal
NATURE COMMUNICATIONS
Volume 14, Issue 1, Pages -Publisher
NATURE PORTFOLIO
DOI: 10.1038/s41467-023-39412-6
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Nuclear factor erythroid 2-related factor 2 (NRF2) is a transcription factor that plays a key role in combating oxidative stress by regulating anti-oxidation gene expression. The deubiquitinase USP25 binds to KEAP1 and prevents its own degradation, leading to the stabilization of NRF2. This study demonstrates that inhibiting or genetically eliminating USP25 attenuates liver damage and reduces mortality rates caused by acetaminophen (APAP) overdose-induced oxidative stress in mice.
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. The redox status of a cell is regulated through a number of mechanisms, chief among these is the KEAP1-mediated ubiquitination and degradation of NRF2. Here the authors show that KEAP1 itself is ubiquitinated and degraded in a process that is opposed by the ubiquitin-specific protease USP25.
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