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KEAP1-NRF2 is a two-component system. In the cytoplasm, NRF2 is ubiquitinated by the KEAP1-CUL3 ubiquitin E3 ligase complex to mark it for degradation by the proteasome. When cells are exposed to electrophiles or reactive oxygen species, KEAP1 is modified and the KEAP1-CUL3 ubiquitin E3 ligase activity declines, which results in the stabilization of NRF2. Stabilized and accumulated NRF2 translocates to the nucleus and activates a battery of cytoprotective genes.
