Kelch-like ECH-associated protein 1–Cullin-3–RING box protein 1 E3 ubiquitin ligase complex (CRL3-KEAP1)

The Kelch-like ECH-associated protein 1–Cullin-3–RING box protein 1 (CRL3-KEAP1) E3 ubiquitin ligase complex is a master regulator of the cellular antioxidant and detoxification response [1, 2, 5]. Under basal conditions, Keap1 functions as a homodimeric substrate adapter that recruits the transcription factor Nrf2 to the Cul3-Rbx1 scaffold, facilitating its polyubiquitination and rapid degradation by the 26S proteasome [5, 7, 8]. Upon exposure to oxidative or electrophilic stress, specific cysteine residues on Keap1 are modified, inducing a conformational change that impairs Nrf2 ubiquitination [1, 5, 13]. This leads to Nrf2 stabilization, nuclear translocation, and the induction of cytoprotective genes [1, 10, 11]. Pharmacological targeting of this complex, primarily through Keap1 inhibition, is a therapeutic strategy for inflammatory, neurodegenerative, and metabolic diseases [2, 4, 6]. However, in oncology, the complex is often disrupted by mutations, leading to constitutive Nrf2 activation that promotes tumor growth and confers resistance to therapy [5, 12, 15].

Other names

Keap1-Cul3-Rbx1 complexKeap1-Nrf2-Cul3 complexKeap1-Cul3 E3 ligaseCullin-RING ligase 3-KEAP1CRL3-KEAP1 complex

The CRL3-KEAP1 complex functions as an E3 ubiquitin ligase where Keap1 acts as a substrate adapter, homodimerizing to recruit Nrf2 to the Cul3-Rbx1 scaffold for polyubiquitination and subsequent proteasomal degradation [1, 2, 5, 8]. Therapeutic agents typically inhibit this complex by either covalently modifying Keap1 cysteine residues (e.g., Cys151) or by non-covalently blocking the Keap1-Nrf2 protein-protein interaction [2, 3, 4]. This inhibition stabilizes Nrf2, allowing it to translocate to the nucleus and activate the transcription of antioxidant response element (ARE)-driven genes [1, 5, 10].