PMID- 29255090
OWN - NLM
STAT- MEDLINE
DCOM- 20190213
LR  - 20230214
IS  - 1083-351X (Electronic)
IS  - 0021-9258 (Print)
IS  - 0021-9258 (Linking)
VI  - 293
IP  - 6
DP  - 2018 Feb 9
TI  - Kelch-like ECH-associated protein 1 (KEAP1) differentially regulates nuclear 
      factor erythroid-2-related factors 1 and 2 (NRF1 and NRF2).
PG  - 2029-2040
LID - 10.1074/jbc.RA117.000428 [doi]
AB  - 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.
CI  - (c) 2018 by The American Society for Biochemistry and Molecular Biology, Inc.
FAU - Tian, Wang
AU  - Tian W
AD  - From the Department of Pharmacology and Toxicology, University of Arizona, 
      Tucson, Arizona 85721.
FAU - Rojo de la Vega, Montserrat
AU  - Rojo de la Vega M
AD  - From the Department of Pharmacology and Toxicology, University of Arizona, 
      Tucson, Arizona 85721.
FAU - Schmidlin, Cody J
AU  - Schmidlin CJ
AD  - From the Department of Pharmacology and Toxicology, University of Arizona, 
      Tucson, Arizona 85721.
FAU - Ooi, Aikseng
AU  - Ooi A
AD  - From the Department of Pharmacology and Toxicology, University of Arizona, 
      Tucson, Arizona 85721.
FAU - Zhang, Donna D
AU  - Zhang DD
AD  - From the Department of Pharmacology and Toxicology, University of Arizona, 
      Tucson, Arizona 85721 dzhang@pharmacy.arizona.edu.
LA  - eng
GR  - P30 CA023074/CA/NCI NIH HHS/United States
GR  - T32 ES007091/ES/NIEHS NIH HHS/United States
GR  - P30 ES006694/ES/NIEHS NIH HHS/United States
GR  - R01 DK109555/DK/NIDDK NIH HHS/United States
GR  - R01 ES026845/ES/NIEHS NIH HHS/United States
GR  - R01 CA154377/CA/NCI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
DEP - 20171218
PL  - United States
TA  - J Biol Chem
JT  - The Journal of biological chemistry
JID - 2985121R
RN  - 0 (KEAP1 protein, human)
RN  - 0 (Kelch-Like ECH-Associated Protein 1)
RN  - 0 (NF-E2-Related Factor 2)
RN  - 0 (NFE2L2 protein, human)
RN  - 0 (NRF1 protein, human)
RN  - 0 (Nuclear Respiratory Factor 1)
SB  - IM
MH  - Amino Acid Motifs
MH  - Cell Line
MH  - Gene Expression Regulation
MH  - Humans
MH  - Kelch-Like ECH-Associated Protein 1/chemistry/genetics/*metabolism
MH  - NF-E2-Related Factor 2/chemistry/genetics/*metabolism
MH  - Nuclear Respiratory Factor 1/chemistry/genetics/*metabolism
MH  - Protein Binding
MH  - Protein Domains
MH  - Protein Stability
MH  - Proteolysis
PMC - PMC5808764
OTO - NOTNLM
OT  - KEAP1
OT  - NRF1
OT  - nuclear factor 2 (erythroid-derived 2-like factor) (NFE2L2) (Nrf2)
OT  - protein degradation
OT  - protein domain
OT  - protein motif
OT  - protein stability
COIS- The authors declare that they have no conflicts of interest with the contents of 
      this article
EDAT- 2017/12/20 06:00
MHDA- 2019/02/14 06:00
PMCR- 2019/02/09
CRDT- 2017/12/20 06:00
PHST- 2017/10/12 00:00 [received]
PHST- 2017/12/04 00:00 [revised]
PHST- 2017/12/20 06:00 [pubmed]
PHST- 2019/02/14 06:00 [medline]
PHST- 2017/12/20 06:00 [entrez]
PHST- 2019/02/09 00:00 [pmc-release]
AID - S0021-9258(20)39850-1 [pii]
AID - RA117.000428 [pii]
AID - 10.1074/jbc.RA117.000428 [doi]
PST - ppublish
SO  - J Biol Chem. 2018 Feb 9;293(6):2029-2040. doi: 10.1074/jbc.RA117.000428. Epub 
      2017 Dec 18.