Cited by 2,224Genomics, phytochemicals, and oxidative stressUbiquitin and proteasome pathwaysRedox biology and oxidative stress

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Oxidative Stress Sensor Keap1 Functions as an Adaptor for Cul3-Based E3 Ligase To Regulate Proteasomal Degradation of Nrf2

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Kobayashi, Akira, Kang, Moon-Il, Okawa, Hiromi, Ohtsuji, Makiko, Zenke, Yukari, Chiba, Tomoki, Igarashi, Kazuhiko, Yamamoto, Masayuki·2004·Molecular and Cellular Biology

DOI 10.1128/mcb.24.16.7130-7139.2004PMC PMC479737

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Abstract

Transcription factor Nrf2 is a major regulator of genes encoding phase 2 detoxifying enzymes and antioxidant stress proteins in response to electrophilic agents and oxidative stress. In the absence of such stimuli, Nrf2 is inactive owing to its cytoplasmic retention by Keap1 and rapid degradation through the proteasome system. We examined the contribution of Keap1 to the rapid turnover of Nrf2 (half-life of less than 20 min) and found that a direct association between Keap1 and Nrf2 is required for Nrf2 degradation. In a series of domain function analyses of Keap1, we found that both the BTB and intervening-region (IVR) domains are crucial for Nrf2 degradation, implying that these two domains act to recruit ubiquitin-proteasome factors. Indeed, Cullin 3 (Cul3), a subunit of the E3 ligase complex, was found to interact specifically with Keap1 in vivo. Keap1 associates with the N-terminal region of Cul3 through the IVR domain and promotes the ubiquitination of Nrf2 in cooperation with the Cul3-Roc1 complex. These results thus provide solid evidence that Keap1 functions as an adaptor of Cul3-based E3 ligase. To our knowledge, Nrf2 and Keap1 are the first reported mammalian substrate and adaptor, respectively, of the Cul3-based E3 ligase system.

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The Role of Nrf2-Mediated Pathway in Cardiac Remodeling and Heart Failure
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Oncogenic functions of the transcription factor Nrf2
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Hyperoxia Stimulates an Nrf2-ARE Transcriptional Response via ROS-EGFR-PI3K-Akt/ERK MAP Kinase Signaling in Pulmonary Epithelial Cells
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PGAM5, a Bcl-XL-interacting protein, is a novel substrate for the redox-regulated Keap1-dependent ubiquitin ligase complex
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Identification of Novel microRNAs in Post-Transcriptional Control of Nrf2 Expression and Redox Homeostasis in Neuronal, SH-SY5Y Cells
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“NRF2 has a very short half-life, which is less than 20 min [9,10].”
Background
Nitric Oxide in Cell Survival: A Janus Molecule
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Molecular basis for the disruption of Keap1–Nrf2 interaction via Hinge & Latch mechanism
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Expression of ABCG2 (BCRP) Is Regulated by Nrf2 in Cancer Cells That Confers Side Population and Chemoresistance Phenotype
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PALB2 Interacts with KEAP1 To Promote NRF2 Nuclear Accumulation and Function
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Retracted
Pro-Oxidant Activity of Flavonoids Induces EpRE-Mediated Gene Expression
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iASPP Is an Antioxidative Factor and Drives Cancer Growth and Drug Resistance by Competing with Nrf2 for Keap1 Binding
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The Nrf2 Pathway in Liver Diseases
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NRF2: KEAPing Tumors Protected
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In defence of ferroptosis
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Authors: Kobayashi, A., Kang, M.-I., Okawa, H., Ohtsuji, M., Zenke, Y., Chiba, T., Igarashi, K., & Yamamoto, M.
Affiliations: University of Tsukuba (JP)
Hiroshima University (JP)
Tokyo Metropolitan Institute of Medical Science (JP)
Corresponding author: Yamamoto, Masayuki
ORCID: Kobayashi, Akira
Zenke, Yukari
Chiba, Tomoki
Igarashi, Kazuhiko
Yamamoto, Masayuki
Venue: Molecular and Cellular Biology
Publisher: Informa UK Limited
Published: 2004-08-01
Volume: 24
Issue: 16
Pages: 7130-7139
ISSN: 0270-7306 (ISSN-L)
1098-5549
DOI: 10.1128/mcb.24.16.7130-7139.2004
PMC: PMC479737
OpenAlex: W2155324869
Cited by: 2,224
References: 33
Citations by year: 2026: 100 · 2025: 102 · 2024: 116 · 2023: 137 · 2022: 154 · 2021: 123 · 2020: 182 · 2019: 121 · 2018: 122 · 2017: 122 · 2016: 140 · 2015: 132 · 2014: 95 · 2013: 100 · 2012: 84
FWCI: 14.20
Type: journal article
Language: en
Open access: green
europepmc.org
Licence: journals.asm.org/non-commercial-tdm-license (tdm)
Locations: Molecular and Cellular Biology (publishedVersion)
Europe PMC (PubMed Central) (publishedVersion)
PubMed Central (publishedVersion)
PubMed (publishedVersion)
Topics: Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics, phytochemicals, and oxidative stress
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ubiquitin and proteasome pathways
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Redox biology and oxidative stress
Keywords: Keap1, Nrf2, CUL3, E3 ubiquitin ligase, adaptor proteins, proteasomal degradation, ubiquitination, BTB domain, ROC1, oxidative stress, antioxidant response
MeSH terms: Kelch-Like ECH-Associated Protein 1, Animals, Cell Line, Cysteine Endopeptidases, DNA-Binding Proteins, Humans, Multienzyme Complexes, Proteins, Recombinant Fusion Proteins, Transcription Factors, Trans-Activators, Protein Structure, Tertiary, Oxidative Stress, Cell Cycle Proteins, Ubiquitin, Ubiquitin-Protein Ligases, Cullin Proteins, Macromolecular Substances, Proteasome Endopeptidase Complex, Intracellular Signaling Peptides and Proteins, Basic-Leucine Zipper Transcription Factors, NF-E2-Related Factor 2, Mice, Fanconi Anemia Complementation Group Proteins

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Oxidative Stress Sensor Keap1 Functions as an Adaptor for Cul3-Based E3 Ligase To Regulate Proteasomal Degradation of Nrf2

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