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. 2019 Sep 10;20(18):4445. doi: 10.3390/ijms20184445

Figure 2.

Figure 2

Schematic representation of the Nrf2–Keap1 signaling mechanism. (a, b and c) Under normal conditions, Keap1 interacts with the ETGE and DLG motifs on Nrf2 and allows Nrf2 to enter the Keap1–Cul3 ubiquitin ligase complex, resulting in the ubiquitination and then degradation of Nrf2; (d) Under stress conditions, the inducer modifies the key cysteine residue of Keap1, leading to the repression of Nrf2 ubiquitination by dissociation inhibitory complexes. In the hinge and latch model, modification of as specific Keap1 cysteine residue results in a conformational change in Keap1, leading to the release of the Nrf2 DLG motif from Keap1. Nrf2 ubiquitination is prevented, but binding to the ETGE domain is still retained, resulting in Nrf2 escaping from the ubiquitination system; (e) Nrf2 protein bypasses Keap1 and moves into the nucleus, interacts with the ARE and stimulates Nrf2 targets. Transcription of genes including quinone oxidoreductase 1 (NQO1), heme oxygenase-1 (HO-1), nicotinamide adenine dinucleotide phosphate (NADPH), glutamate–cysteine ligase (GCL), superoxide dismutase (SOD), glycopeptide peroxidase (GPx), increases the defense of cells against oxidative stress.