Keap1 (Kelch-like ECH-associated protein 1) is a critical intracellular sensor and regulator of the Nrf2/ARE (antioxidant response element) signaling pathway. Keap1 is an adaptor protein for the Cul3-based E3 ubiquitin ligase complex, responsible for targeting Nrf2 (nuclear factor erythroid 2-related factor 2) for ubiquitination and proteasomal degradation. It contains 27 cysteine residues that can be modified by oxidative stress, leading to the dissociation of Nrf2 and its subsequent stabilization and nuclear translocation. Under normal conditions, Keap1 binds to Nrf2, targeting it for degradation. However, in response to oxidative stress, certain cysteine residues in Keap1 are modified, inhibiting its ubiquitin ligase activity and leading to Nrf2 accumulation in the nucleus where it activates the transcription of antioxidant and detoxifying genes. Mutations in Keap1 or its interaction with Nrf2 have been implicated in various diseases, including cancer, where somatic mutations in cancer cells occur with high frequency in the DLGex and ETGE motifs of Nrf2, disrupting the Keap1-Nrf2 binding and leading to constitutive accumulation of Nrf2, which supports malignant growth.
中文
