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. Author manuscript; available in PMC: 2022 Sep 1.
Published in final edited form as: Cancer Discov. 2022 Mar 1;12(3):625–643. doi: 10.1158/2159-8290.CD-21-0922

Figure 1: Physiological Activation and Regulation of NRF2.

Figure 1:

Under basal conditions, NRF2 is bound by KEAP1 via the DLG and ETGE motifs in the Neh2 domain of NRF2 in cytosol and leads to binding of CUL3, poly-ubiquitination and proteasomal degradation. NRF2 is also regulated by KEAP1-indepent mechanisms via phosphorylation of the Neh6 domain by GSK-3 and proteasomal degradation by β-TrCP. Reactive oxygen species (ROS), drugs, and toxins react with cysteine residues on KEAP1 resulting in structural changes and the accumulation of NRF2 to translocate to the nucleus and function as a transcriptional factor. In the nucleus, NRF2 heterodimerizes with small MAF proteins and binds to antioxidant response elements to induce a series of target genes for detoxification of ROS, toxins, and drugs.

KEAP1, Kelch-like ECH-associated protein 1; NRF2, nuclear factor erythroid 2-related factor 2; β-TrCP, beta-transducin repeat containing protein; GSK-3, glycogen synthase kinase 3; Ub, ubiquitin; ARE, antioxidant response element; MAF, musculoaponeurotic fibrosarcoma; TXN, thioredoxin; TXNRD1, thioredoxin reductase 1; PRDX1, peroxiredoxin-1; GCLC, glutamate-cysteine ligase catalytic subunit; GCLM, glutamate-cysteine ligase modifier subunit; NQO1, NADPH-quinone Dehydrogenase 1; ABC, ATP-binding cassette