KEAP1Nrf2

Keap1-Nrf2 is a cellular signaling axis formed by Kelch-like ECH-associated protein 1 (Keap1) and the transcription factor Nrf2 (NFE2L2). It serves as the principal regulator of the antioxidant response, coupling redox sensing to the transcriptional activation of cytoprotective genes.

Under basal conditions Keap1 acts as a substrate adaptor for a Cul3-based E3 ubiquitin ligase complex. Nrf2 contains an N-terminal Neh2 domain with two Keap1-binding motifs, DLG and ETGE. Keap1 binds Nrf2 in a 1:1 complex and promotes ubiquitination and rapid proteasomal degradation, keeping Nrf2 levels low.

During oxidative or electrophilic stress, cysteine residues on Keap1 (notably Cys151, Cys273, Cys288) become modified. This alters Keap1’s conformation and its ability to target Nrf2 for degradation, leading to stabilization and accumulation of Nrf2 in the cytoplasm. Nrf2 then translocates to the nucleus, dimerizes with small Maf proteins, and binds antioxidant response element (ARE) sequences in the promoters of target genes. This induces transcription of phase II detoxification enzymes and antioxidant proteins such as NQO1, HMOX1 (HO-1), GCLC, GCLM, GSTs, and various glutathione-related enzymes, among others. The induced gene set enhances cellular redox capacity and detoxification.

Regulation of the axis is multifaceted. In addition to cysteine modification, kinases can modulate Nrf2 activity; there is a proposed “hinge and latch” mechanism for the Keap1–Nrf2 interaction. There are Keap1-dependent and Keap1-independent routes to Nrf2 regulation; chronic deregulation, including KEAP1 or NFE2L2 mutations, is linked to cancer and inflammatory diseases. Pharmacological activators that modify Keap1 cysteines are studied for cytoprotective effects; however, sustained Nrf2 activation may have deleterious consequences in cancer.