Kelch-like ECH-associated protein 1–Nuclear factor erythroid 2-related factor 2 protein–protein interaction (Keap1–Nrf2 PPI)

The Kelch-like ECH-associated protein 1–Nuclear factor erythroid 2-related factor 2 (Keap1–Nrf2) protein–protein interaction serves as the primary cellular defense mechanism against oxidative and electrophilic stress (Yamamoto et al., 2018, PMID: 29717933). Under basal conditions, Keap1 (UniProt Q14145) functions as a substrate adapter for the Cullin 3-RING E3 ubiquitin ligase complex, which targets Nrf2 (UniProt Q16236) for constant ubiquitination and proteasomal degradation. When cells encounter stress, reactive species modify critical cysteine residues on Keap1, disrupting the interaction and allowing Nrf2 to accumulate and translocate to the nucleus (Lu et al., 2016, PMID: 26530614). In the nucleus, Nrf2 binds to Antioxidant Response Elements (ARE) to induce the expression of cytoprotective genes such as HMOX1 and NQO1. Therapeutic targeting of this interaction, using drugs like Omaveloxolone (FDA approved for Friedreich's ataxia) or Dimethyl fumarate, aims to boost antioxidant capacity in diseases like neurodegeneration and chronic kidney disease. However, the "Nrf2 paradox" remains a concern, as constitutive Nrf2 activation can promote the survival and chemoresistance of certain cancer cells (PMID: 30735919).

Other names

Keap1-Nrf2 axisKeap1-Nrf2 pathwayKelch-like ECH-associated protein 1-Nuclear factor erythroid 2-related factor 2 interactionKeap1-Nrf2-ARE pathway

Inhibition of the Keap1–Nrf2 protein–protein interaction, either through covalent modification of Keap1 cysteine residues or non-covalent competitive binding to the Keap1 Kelch domain, which prevents Nrf2 ubiquitination and degradation, thereby promoting Nrf2-mediated antioxidant gene expression (Yamamoto et al., 2018).