Nrf2 is controlled by two distinct β-TrCP recognition motifs in its Neh6 domain, one of which can be modulated by GSK-3 activity

Chowdhry, S; Zhang, Y; McMahon, M; Sutherland, C; Cuadrado, A; Hayes, J D

doi:10.1038/onc.2012.388

Cited by 657Genomics, phytochemicals, and oxidative stressUbiquitin and proteasome pathwaysNF-κB Signaling Pathways

Nrf2 is controlled by two distinct β-TrCP recognition motifs in its Neh6 domain, one of which can be modulated by GSK-3 activity

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Chowdhry, S, Zhang, Y, McMahon, M, Sutherland, C, Cuadrado, A, Hayes, J D·2013·Oncogene

DOI 10.1038/onc.2012.388PMC PMC3522573

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Abstract

Identification of regulatable mechanisms by which transcription factor NF-E2 p45-related factor 2 (Nrf2) is repressed will allow strategies to be designed that counter drug resistance associated with its upregulation in tumours that harbour somatic mutations in Kelch-like ECH-associated protein-1 (Keap1), a gene that encodes a joint adaptor and substrate receptor for the Cul3-Rbx1/Roc1 ubiquitin ligase. We now show that mouse Nrf2 contains two binding sites for β-transducin repeat-containing protein (β-TrCP), which acts as a substrate receptor for the Skp1-Cul1-Rbx1/Roc1 ubiquitin ligase complex. Deletion of either binding site in Nrf2 decreased β-TrCP-mediated ubiquitylation of the transcription factor. The ability of one of the two β-TrCP-binding sites to serve as a degron could be both increased and decreased by manipulation of glycogen synthase kinase-3 (GSK-3) activity. Biotinylated-peptide pull-down assays identified DSGIS(338) and DSAPGS(378) as the two β-TrCP-binding motifs in Nrf2. Significantly, our pull-down assays indicated that β-TrCP binds a phosphorylated version of DSGIS more tightly than its non-phosphorylated counterpart, whereas this was not the case for DSAPGS. These data suggest that DSGIS, but not DSAPGS, contains a functional GSK-3 phosphorylation site. Activation of GSK-3 in Keap1-null mouse embryonic fibroblasts (MEFs), or in human lung A549 cells that contain mutant Keap1, by inhibition of the phosphoinositide 3-kinase (PI3K)-protein kinase B (PKB)/Akt pathway markedly reduced endogenous Nrf2 protein and decreased to 10-50% of normal the levels of mRNA for prototypic Nrf2-regulated enzymes, including the glutamate-cysteine ligase catalytic and modifier subunits, glutathione S-transferases Alpha-1 and Mu-1, haem oxygenase-1 and NAD(P)H:quinone oxidoreductase-1. Pre-treatment of Keap1(-/-) MEFs or A549 cells with the LY294002 PI3K inhibitor or the MK-2206 PKB/Akt inhibitor increased their sensitivity to acrolein, chlorambucil and cisplatin between 1.9-fold and 3.1-fold, and this was substantially attenuated by simultaneous pre-treatment with the GSK-3 inhibitor CT99021.

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The Neh6 domain is a redox-insensitive degron that provides Keap1-independent negative Nrf2 regulation and contains DSGIS and DSAPGS motifs to which βTrCP binds, with the DSGIS motif containing a GSK3 phosphorylation site that enhances βTrCP activity.
“The Neh6 domain is a redox-insensitive degron that provides Keap1-independent negative Nrf2 regulation. Similar to Neh2, Neh6 contains two highly conserved 334DSGIS338 and 373DSAPGS378 motifs to which the β-transducin repeat-containing protein (βTrCP) binds, and within the DSGIS motif, a phosphorylation site for glycogen synthase kinase-3 (GSK3) that enhances βTrCP activity upon GSK3-mediated ph”
From Nrf2 and Oxidative Stress: A General Overview of Mechanisms and Implications in Human Disease (2022) · cites this paper as [63]

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Authors: Chowdhry, S., Zhang, Y., McMahon, M., Sutherland, C., Cuadrado, A., & Hayes, J. D.
Affiliations: University of Dundee (GB)
Biomedical Research Networking Center on Neurodegenerative Diseases (ES)
Corresponding author: Hayes, J D
ORCID: Chowdhry, S
Zhang, Y
McMahon, M
Sutherland, C
Cuadrado, A
Hayes, J D
Venue: Oncogene
Publisher: Springer Science and Business Media LLC
Published: 2012-09-10
Volume: 32
Issue: 32
Pages: 3765-3781
ISSN: 0950-9232 (ISSN-L)
1476-5594
DOI: 10.1038/onc.2012.388
PMC: PMC3522573
OpenAlex: W2038612772
Cited by: 657
References: 64
Citations by year: 2026: 46 · 2025: 51 · 2024: 54 · 2023: 60 · 2022: 64 · 2021: 58 · 2020: 64 · 2019: 35 · 2018: 39 · 2017: 45 · 2016: 36 · 2015: 50 · 2014: 37 · 2013: 15 · 2012: 3
FWCI: 13.49
Type: journal article
Language: en
Open access: hybrid
doi.org
Licence: cc-by-nc-sa
creativecommons.org/licenses/by-nc-sa/3.0/ (tdm)
Locations: Oncogene (publishedVersion, cc-by-nc-sa)
PubMed (publishedVersion)
Europe PMC (PubMed Central) (acceptedVersion)
PubMed Central (acceptedVersion)
DIGITAL.CSIC (Spanish National Research Council (CSIC)) (submittedVersion)
Discovery Research Portal (University of Dundee) (submittedVersion)
Funders: Cancer Research UK (C4909/A9990, A7161, A13786, A5942, 13786, A9990, C4909/A13786)
Tenovus
Biotechnology and Biological Sciences Research Council (C18727)
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 › Cancer Research › NF-κB Signaling Pathways
Keywords: Nrf2, β-TrCP, GSK3 phosphorylation, Keap1, ubiquitin ligase, protein degradation, degron, PI3K/Akt signaling, glutathione S-transferase, heme oxygenase-1, NQO1, acrolein, drug resistance, cancer cells
MeSH terms: Kelch-Like ECH-Associated Protein 1, Animals, Antineoplastic Agents, Binding Sites, Humans, Phosphorylation, Protein Structure, Tertiary, Phosphatidylinositol 3-Kinases, Glycogen Synthase Kinase 3, beta-Transducin Repeat-Containing Proteins, Intracellular Signaling Peptides and Proteins, Extracellular Signal-Regulated MAP Kinases, p38 Mitogen-Activated Protein Kinases, NF-E2-Related Factor 2, Mice, Ubiquitination

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Nrf2 is controlled by two distinct β-TrCP recognition motifs in its Neh6 domain, one of which can be modulated by GSK-3 activity

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