Oxidative and electrophilic stresses activate Nrf2 by inhibiting the ubiquitination activity of Keap1. The Keap1-Nrf2 system regulates cytoprotective gene expression in response to oxidative and electrophilic stresses. Under normal conditions, Keap1 suppresses Nrf2 activity, but oxidative or electrophilic stresses inhibit Keap1's ability to ubiquitinate Nrf2, leading to its nuclear accumulation. This process is not due to the dissociation of Nrf2 from Keap1, but rather by impairing Keap1-mediated proteasomal degradation of Nrf2. The cysteine residues Cys273 and Cys288 in Keap1 are crucial for its repression activity, and their modification or mutation does not affect the association between Keap1 and Nrf2, but impairs the ubiquitination of Nrf2 by the Keap1-Cul3 complex. This results in the nuclear accumulation of Nrf2, which then activates the expression of cytoprotective genes. The study also shows that oxidative and electrophilic stresses do not dissociate the Keap1-Nrf2 complex, but instead affect the ubiquitination activity of the complex. The findings suggest that the sensor for oxidative and electrophilic stresses is closely linked to the degradation system of Nrf2. The study provides a detailed molecular mechanism of how oxidative and electrophilic stresses activate Nrf2 through the inhibition of Keap1's ubiquitination activity.Oxidative and electrophilic stresses activate Nrf2 by inhibiting the ubiquitination activity of Keap1. The Keap1-Nrf2 system regulates cytoprotective gene expression in response to oxidative and electrophilic stresses. Under normal conditions, Keap1 suppresses Nrf2 activity, but oxidative or electrophilic stresses inhibit Keap1's ability to ubiquitinate Nrf2, leading to its nuclear accumulation. This process is not due to the dissociation of Nrf2 from Keap1, but rather by impairing Keap1-mediated proteasomal degradation of Nrf2. The cysteine residues Cys273 and Cys288 in Keap1 are crucial for its repression activity, and their modification or mutation does not affect the association between Keap1 and Nrf2, but impairs the ubiquitination of Nrf2 by the Keap1-Cul3 complex. This results in the nuclear accumulation of Nrf2, which then activates the expression of cytoprotective genes. The study also shows that oxidative and electrophilic stresses do not dissociate the Keap1-Nrf2 complex, but instead affect the ubiquitination activity of the complex. The findings suggest that the sensor for oxidative and electrophilic stresses is closely linked to the degradation system of Nrf2. The study provides a detailed molecular mechanism of how oxidative and electrophilic stresses activate Nrf2 through the inhibition of Keap1's ubiquitination activity.