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    Kelch-like ECH-associated protein 1 (KEAP1) differentially regulates nuclear factor erythroid-2–related factors 1 and 2 (NRF1 and NRF2)

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    J.Biol.Chem.-2018-Tian-2029-40.pdf
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    Author
    Tian, Wang
    de la Vega, Montserrat Rojo
    Schmidlin, Cody J.
    Ooi, Aikseng
    Zhang, Donna D.
    Affiliation
    Univ Arizona, Dept Pharmacol & Toxicol
    Issue Date
    2018-02-09
    Keywords
    protein degradation
    protein domain
    protein motif
    protein stability
    nuclear factor 2 (erythroid-derived 2-like factor) (NFE2L2) (Nrf2)
    KEAP1
    NRF1
    
    Metadata
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    Publisher
    AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
    Citation
    Kelch-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
    Journal
    Journal of Biological Chemistry
    Rights
    © 2018 by The American Society for Biochemistry and Molecular Biology, Inc.
    Collection Information
    This 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 repository@u.library.arizona.edu.
    Abstract
    Nuclear 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.
    Note
    12 month embargo; published online: 18 December 2017
    ISSN
    0021-9258
    1083-351X
    PubMed ID
    29255090
    DOI
    10.1074/jbc.RA117.000428
    Version
    Final published version
    Sponsors
    National Institutes of Health [R01 CA154377, R01 DK109555, R01 ES026845]
    Additional Links
    http://www.jbc.org/lookup/doi/10.1074/jbc.RA117.000428
    ae974a485f413a2113503eed53cd6c53
    10.1074/jbc.RA117.000428
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    • Issue date: 2006 Nov 1
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