KEAP1

KEAP1 (Kelch-like ECH-associated protein 1) is a cysteine-rich BTB-BACK-Kelch protein that functions as the principal substrate adaptor of the BCR(KEAP1) E3 ubiquitin ligase complex (CUL3-RBX1-KEAP1). In its homodimeric form, KEAP1 binds the Neh2 domain of NRF2 (NFE2L2) via two degron motifs (ETGE and DLG) and targets NRF2 for polyubiquitination and proteasomal degradation under basal conditions. KEAP1 contains reactive cysteine residues (especially Cys151, Cys273, Cys288) that act as sensors for electrophiles and oxidative stress. Upon covalent modification of these cysteines by electrophilic compounds (sulforaphane, itaconate, etc.) or reactive oxygen species, the E3 ligase activity is inhibited, allowing NRF2 to accumulate and translocate to the nucleus to activate cytoprotective genes via antioxidant response elements (AREs). KEAP1 is primarily cytoplasmic and is also regulated by autophagy through interaction with SQSTM1/p62, which sequesters KEAP1 in inclusion bodies. Loss-of-function mutations in KEAP1 are frequent in lung cancer and lead to constitutive NRF2 activation, promoting tumor growth and chemoresistance.

Disorders

Relationship is the entry's genetic[].relationship_type. untyped means the entry has a genetic record for the gene but does not type it; its free-text association is shown instead.