Q14145

Keap1 (kelch-like ECH-associated protein 1, INrf2, KLHL19) is a stress sensing adaptor for the Cullin3 (Cul3)-dependent E3 ubiquitin ligase complex that negatively regulates Nrf2 (NF-E2-related factor 2). Steady state levels of proteins are under the influence of the ubiquitin pathway, which consists of ubiquitin activation (E1), conjugation (E2) and ligation (E3). Keap1 assembles into an E3 ubiquitin ligase complex with Cul3 and Rbx1 and targets lysine residues in the N-terminal Neh2 domain of Nrf2 for ubiquitin conjugation. The Keap1-Nrf2 system mediates cytoprotective gene expression in response to oxidative and/or electrophilic stresses. Keap1 constitutively suppresses Nrf2 activity under unstressed conditions, oxidants or electrophiles provoke the repression of Keap1 activity, inducing Nrf2 activation. Cys 273 and Cys 288 residues of Keap1 are required for suppressing Nrf2 nuclear accumulation. Keap1 sequesters Nrf2 in the cytoplasm through an active Crm1/exportin-dependent nuclear export mechanism.