Keap1mediated

Keap1-mediated regulation refers to the control of the transcription factor Nrf2 by the cysteine-rich protein Keap1 in the cellular response to oxidative and electrophilic stress. Keap1 (Kelch-like ECH-associated protein 1) acts as a substrate adaptor for a Cullin 3 (Cul3)–Rbx1 E3 ubiquitin ligase complex, promoting ubiquitination and proteasomal degradation of Nrf2 under basal conditions. In this arrangement, Nrf2 is kept at low cellular levels, preventing unnecessary activation of antioxidant defenses.

Mechanistically, Nrf2 contains an N-terminal Neh2 domain with DLG and ETGE motifs that bind Keap1. The interaction is often described by a hinge-and-latch model, whereby Keap1 bridges Nrf2 to the Cul3 ubiquitin ligase, leading to Nrf2 ubiquitination and turnover. Upon exposure to oxidative or electrophilic stress, cysteine residues on Keap1 (notably Cys151, Cys273, and Cys288) become modified, causing conformational changes that impair Nrf2 ubiquitination. This results in stabilization and accumulation of Nrf2, which then translocates to the nucleus.

In the nucleus, Nrf2 dimerizes with small Maf proteins and binds antioxidant response elements (ARE) in the promoters of target genes. This activates transcription of cytoprotective and detoxification enzymes such as NQO1, HO-1, GCLC, GCLM, and various GSTs, coordinating a broad cellular defense program.

Keap1-mediated signaling is also influenced by autophagy-related processes; for example, p62 can bind Keap1 and promote its degradation, further activating Nrf2. Dysregulation of this axis through KEAP1 or NFE2L2 mutations can contribute to cancer progression and chemoresistance, while therapeutic strategies target this pathway for neuroprotection and anti-inflammatory aims. Overall, Keap1-mediated regulation of Nrf2-ARE signaling is a central mechanism for maintaining redox homeostasis.