English: Figure 1  KEAP1/NRF2 signaling pathway. (a) NRF2 and KEAP1 protein domains. KEAP1 contains an amino-terminal region (NTR; purple), a broad complex/Tramtrack/Bric-à-brac (BTB; blue) domain, an intervening region (IVR; yellow), six Kelch domains (red), and the C-terminal region (CTR; orange). Annotated across KEAP1 are cysteine residues posttranslationally modified to enable NRF2 activation. NRF2 contains seven NRF2-ECH homology (Neh; green) domains. Highlighted in red in the Neh2 domain are the two most frequently mutated NRF2 codons, DLG and ETGE. (b) KEAP1 homodimerizes through the BTB domain, and through the Kelch domains KEAP1 interacts with NRF2 at the ETGE and DLG motifs. KEAP1 binds CUL3 (Cullin 3) and RBX1 (RING box 1) to form an E3 ubiquitin ligase complex that ubiquitinates NRF2 and promotes its proteasomal degradation in the cytoplasm. Multiple posttranslational modifications on KEAP1 cysteines by reactive oxygen species (ROS) or electrophiles (see Table 1) lead to stabilization and release of NRF2 from KEAP1 and the nuclear translocation of NRF2. Additionally, p62 can bind to KEAP1 and sequester it from NRF2, therefore leading to NRF2 stabilization. Phosphorylation of NRF2 can also lead to its release from KEAP1. Upon stabilization, NRF2 enters the nucleus where it dimerizes with the transcriptional activator MAF and induces expression of target genes that contain the ARE (antioxidant response element) motif.