| First Author | Suzuki T | Year | 2019 |
| Journal | Cell Rep | Volume | 28 |
| Issue | 3 | Pages | 746-758.e4 |
| PubMed ID | 31315052 | Mgi Jnum | J:284404 |
| Mgi Id | MGI:6381058 | Doi | 10.1016/j.celrep.2019.06.047 |
| Citation | Suzuki T, et al. (2019) Molecular Mechanism of Cellular Oxidative Stress Sensing by Keap1. Cell Rep 28(3):746-758.e4 |
| abstractText | 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. |
