RRC ID 57611
Author Suzuki T, Muramatsu A, Saito R, Iso T, Shibata T, Kuwata K, Kawaguchi SI, Iwawaki T, Adachi S, Suda H, Morita M, Uchida K, Baird L, Yamamoto M.
Title Molecular Mechanism of Cellular Oxidative Stress Sensing by Keap1.
Journal Cell Rep
Abstract The Keap1-Nrf2 system plays a central role in the oxidative stress response; however, the identity of the reactive oxygen species sensor within Keap1 remains poorly understood. Here, we show that a Keap1 mutant lacking 11 cysteine residues retains the ability to target Nrf2 for degradation, but it is unable to respond to cysteine-reactive Nrf2 inducers. Of the 11 mutated cysteine residues, we find that 4 (Cys226/613/622/624) are important for sensing hydrogen peroxide. Our analyses of multiple mutant mice lines, complemented by MEFs expressing a series of Keap1 mutants, reveal that Keap1 uses the cysteine residues redundantly to set up an elaborate fail-safe mechanism in which specific combinations of these four cysteine residues can form a disulfide bond to sense hydrogen peroxide. This sensing mechanism is distinct from that used for electrophilic Nrf2 inducers, demonstrating that Keap1 is equipped with multiple cysteine-based sensors to detect various endogenous and exogenous stresses.
Volume 28(3)
Pages 746-758.e4
Published 2019-7-16
DOI 10.1016/j.celrep.2019.06.047
PII S2211-1247(19)30820-4
PMID 31315052
MeSH Animals Cysteine / metabolism* HEK293 Cells Humans Hydrogen Peroxide / metabolism* Kelch-Like ECH-Associated Protein 1 / chemistry Kelch-Like ECH-Associated Protein 1 / genetics* Kelch-Like ECH-Associated Protein 1 / metabolism* Mice Mice, Inbred C57BL Mice, Knockout Mutation NF-E2 Transcription Factor / genetics NF-E2 Transcription Factor / metabolism Oxidative Stress / genetics* Oxidative Stress / physiology
IF 7.815
Times Cited 17
Mice RBRC05704