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Keap1 represses nuclear activation of antioxidant responsive elements by Nrf2 through binding to the amino-terminal Neh2 domain
Open accessAbstract
Transcription factor Nrf2 is essential for the antioxidant responsive element (ARE)-mediated induction of phase II detoxifying and oxidative stress enzyme genes. Detailed analysis of differential Nrf2 activity displayed in transfected cell lines ultimately led to the identification of a new protein, which we named Keap1, that suppresses Nrf2 transcriptional activity by specific binding to its evolutionarily conserved amino-terminal regulatory domain. The closest homolog of Keap1 is a Drosophila actin-binding protein called Kelch, implying that Keap1 might be a Nrf2 cytoplasmic effector. We then showed that electrophilic agents antagonize Keap1 inhibition of Nrf2 activity in vivo, allowing Nrf2 to traverse from the cytoplasm to the nucleus and potentiate the ARE response. We postulate that Keap1 and Nrf2 constitute a crucial cellular sensor for oxidative stress, and together mediate a key step in the signaling pathway that leads to transcriptional activation by this novel Nrf2 nuclear shuttling mechanism. The activation of Nrf2 leads in turn to the induction of phase II enzyme and antioxidative stress genes in response to electrophiles and reactive oxygen species.
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“The N-terminal Neh2 domain is a redox-sensitive degron that negatively regulates Nrf2 activity and contains two highly conserved 29DLG31 and 79ETGE82 motifs to which Keap1 binds, as well as seven lysine residues that are targets for ubiquitination by the Cul3 E3 ubiquitin ligase [49,65].”
From Nrf2 and Oxidative Stress: A General Overview of Mechanisms and Implications in Human Disease (2022) · cites this paper as [49]
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“Nrf2 regulates the expression of a multitude of antioxidant and phase II enzyme genes and is negatively regulated by Kelch-like ECH-associated protein (Keap1) [49], a substrate adaptor protein that binds to Nrf2 in the cytosol to facilitate its polyubiquitination by the Cullin 3 (Cul3) E3 ubiquitin ligase for proteasomal degradation [50,51,52].”
From Nrf2 and Oxidative Stress: A General Overview of Mechanisms and Implications in Human Disease (2022) · cites this paper as [49]
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Self-citationNatural Nrf2 Modulators for Skin Protection
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“NRF2 is negatively regulated by KEAP1 (Kelch-like ECH47 associated protein 1), a substrate adaptor protein for the cullin 3 (CUL3)-based E3 ubiquitin ligase that 48 facilitates NRF2 ubiquitination and proteasomal degradation in the absence of oxidative or xenobiotic 49 stress (3).”
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Metadata
- Authors
- Itoh, K., Wakabayashi, N., Katoh, Y., Ishii, T., Igarashi, K., Engel, J. D., & Yamamoto, M.
- Affiliations
- University of Tsukuba (JP)
- Northwestern University (US)
- Venue
- Genes & Development
- Publisher
- Cold Spring Harbor Laboratory
- Published
- 1999-01-01
- Volume
- 13
- Issue
- 1
- Pages
- 76-86
- ISSN
- 0890-9369 (ISSN-L)
- 1549-5477
- PMC
- PMC316370
- OpenAlex
- W2115338196
- Cited by
- 3,634
- References
- 46
- Citations by year
- 2026: 141 · 2025: 162 · 2024: 177 · 2023: 196 · 2022: 222 · 2021: 184 · 2020: 217 · 2019: 196 · 2018: 187 · 2017: 197 · 2016: 177 · 2015: 177 · 2014: 167 · 2013: 162 · 2012: 142
- Type
- posted content
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Genes & Development (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Cancer Institute (R01CA080088, CA 80088)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics, phytochemicals, and oxidative stress
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Redox biology and oxidative stress
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Glutathione Transferases and Polymorphisms
- Keywords
- Keap1, Nrf2, antioxidant response element, oxidative stress sensing, phase II enzymes, reactive oxygen species, transcriptional repression, oxidative stress response
- MeSH terms
- Amino Acid Sequence, Animals, Antioxidants, Birds, Carrier Proteins, Cell Line, DNA-Binding Proteins, Fungal Proteins, Gene Expression Regulation, Luminescent Proteins, Molecular Sequence Data, Protein Binding, Recombinant Fusion Proteins, Transcription Factors, Transfection, Transcriptional Activation, Trans-Activators, Conserved Sequence, Sequence Homology, Amino Acid, Genes, Reporter, Oxidative Stress, Saccharomyces cerevisiae Proteins, Green Fluorescent Proteins, NF-E2-Related Factor 2
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