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

The Keap1–Nrf2 complex is a primary cellular defense mechanism against oxidative and electrophilic stress. Kelch-like ECH-associated protein 1 (Keap1) functions as a substrate adapter for the Cullin 3 (Cul3)-containing E3 ubiquitin ligase complex, which targets Nuclear factor erythroid 2-related factor 2 (Nrf2) for polyubiquitination and subsequent proteasomal degradation under homeostatic conditions (Yamamoto et al., 2018, Physiological Reviews). When cells encounter oxidative stress or electrophiles, critical cysteine residues on Keap1 (notably Cys151, Cys273, and Cys288) are modified, causing a conformational change that disrupts the Keap1–Nrf2 interaction (Saito et al., 2016, Advances in Biological Regulation). This stabilization allows Nrf2 to accumulate, translocate to the nucleus, and heterodimerize with small Maf proteins to bind Antioxidant Response Elements (ARE) in the promoter regions of over 200 cytoprotective genes (Itoh et al., 1997, Genes & Development). These genes encode proteins involved in glutathione synthesis, redox homeostasis, and xenobiotic metabolism, such as Heme oxygenase 1 (HMOX1) and NAD(P)H quinone dehydrogenase 1 (NQO1). Pharmacological modulation of this complex, primarily through Nrf2 activators like Omaveloxolone and Dimethyl fumarate, is utilized to treat neurodegenerative and inflammatory diseases, though concerns remain regarding the potential for Nrf2 to support the survival of established cancer cells (Rojo de la Vega et al., 2018, Cancer Cell).

Other names

Keap1-Nrf2 pathwayKeap1-Nfe2l2 complexINrf2-Nrf2 complexKelch-like ECH-associated protein 1-Nuclear factor erythroid 2-related factor 2 signaling module

Nrf2 activation via inhibition of Keap1-mediated degradation, typically through electrophilic modification of Keap1 cysteine residues (e.g., Cys151) or disruption of the Keap1-Nrf2 protein-protein interaction (PPI).