Kelch-like ECH-associated protein 1 (KEAP1) differentially regulates nuclear factor erythroid-2–related factors 1 and 2 (NRF1 and NRF2)
AffiliationUniv Arizona, Dept Pharmacol & Toxicol
nuclear factor 2 (erythroid-derived 2-like factor) (NFE2L2) (Nrf2)
MetadataShow full item record
CitationKelch-like ECH-associated protein 1 (KEAP1) differentially regulates nuclear factor erythroid-2–related factors 1 and 2 (NRF1 and NRF2) 2018, 293 (6):2029 Journal of Biological Chemistry
JournalJournal of Biological Chemistry
Rights© 2018 by The American Society for Biochemistry and Molecular Biology, Inc.
Collection InformationThis item from the UA Faculty Publications collection is made available by the University of Arizona with support from the University of Arizona Libraries. If you have questions, please contact us at email@example.com.
AbstractNuclear factor erythroid-2-related factor 1 (NRF1) and NRF2 are essential for maintaining redox homeostasis and coordinating cellular stress responses. They are highly homologous transcription factors that regulate the expression of genes bearing antioxidant-response elements (AREs). Genetic ablation of NRF1 or NRF2 results in vastly different phenotypic outcomes, implying that they play different roles and may be differentially regulated. Kelch-like ECH-associated protein 1 (KEAP1) is the main negative regulator of NRF2 and mediates ubiquitylation and degradation of NRF2 through its NRF2-ECH homology-like domain 2 (Neh2). Here, we report that KEAP1 binds to the Neh2-like (Neh2L) domain of NRF1 and stabilizes it. Consistently, NRF1 is more stable in KEAP1(+/+) than in KEAP1(-/-) isogenic cell lines, whereas NRF2 is dramatically stabilized in KEAP1(-/-) cells. Replacing NRF1's Neh2L domain with NRF2's Neh2 domain renders NRF1 sensitive to KEAP1-mediated degradation, indicating that the amino acids between the DLG and ETGE motifs, not just the motifs themselves, are essential for KEAP1-mediated degradation. Systematic site-directed mutagenesis identified the core amino acid residues required for KEAP1-mediated degradation and further indicated that the DLG and ETGE motifs with correct spacing are insufficient as a KEAP1 degron. Our results offer critical insights into our understanding of the differential regulation of NRF1 and NRF2 by KEAP1 and their different physiological roles.
Note12 month embargo; published online: 18 December 2017
VersionFinal published version
SponsorsNational Institutes of Health [R01 CA154377, R01 DK109555, R01 ES026845]
- Negative regulation of the Nrf1 transcription factor by its N-terminal domain is independent of Keap1: Nrf1, but not Nrf2, is targeted to the endoplasmic reticulum.
- Authors: Zhang Y, Crouch DH, Yamamoto M, Hayes JD
- Issue date: 2006 Nov 1
- Evolutionary conserved N-terminal domain of Nrf2 is essential for the Keap1-mediated degradation of the protein by proteasome.
- Authors: Katoh Y, Iida K, Kang MI, Kobayashi A, Mizukami M, Tong KI, McMahon M, Hayes JD, Itoh K, Yamamoto M
- Issue date: 2005 Jan 15
- Keap1 recruits Neh2 through binding to ETGE and DLG motifs: characterization of the two-site molecular recognition model.
- Authors: Tong KI, Katoh Y, Kusunoki H, Itoh K, Tanaka T, Yamamoto M
- Issue date: 2006 Apr
- Redox-regulated turnover of Nrf2 is determined by at least two separate protein domains, the redox-sensitive Neh2 degron and the redox-insensitive Neh6 degron.
- Authors: McMahon M, Thomas N, Itoh K, Yamamoto M, Hayes JD
- Issue date: 2004 Jul 23
- Different electrostatic potentials define ETGE and DLG motifs as hinge and latch in oxidative stress response.
- Authors: Tong KI, Padmanabhan B, Kobayashi A, Shang C, Hirotsu Y, Yokoyama S, Yamamoto M
- Issue date: 2007 Nov
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