Succinylation of a KEAP1 sensor lysine promotes NRF2 activation.
Journal
Cell chemical biology
ISSN: 2451-9448
Titre abrégé: Cell Chem Biol
Pays: United States
ID NLM: 101676030
Informations de publication
Date de publication:
19 10 2023
19 10 2023
Historique:
received:
27
04
2023
revised:
04
07
2023
accepted:
30
07
2023
pmc-release:
19
10
2024
medline:
26
10
2023
pubmed:
25
8
2023
entrez:
24
8
2023
Statut:
ppublish
Résumé
Cross talk between metabolism and stress-responsive signaling is essential for maintaining cellular homeostasis. This cross talk is often achieved through covalent modification of proteins by endogenous, reactive metabolites that regulate key stress-responsive transcription factors like NRF2. Metabolites including methylglyoxal, glyceraldehyde 3-phosphate, fumarate, and itaconate covalently modify sensor cysteines of the NRF2 repressor KEAP1, resulting in stabilization of NRF2 and activation of its cytoprotective transcriptional program. Here, we employed a shRNA-based screen targeting the enzymes of central carbon metabolism to identify additional regulatory nodes bridging metabolism to NRF2 activation. Succinic anhydride, increased by genetic depletion of the TCA cycle enzyme succinyl-CoA synthetase or by direct administration, results in N-succinylation of lysine 131 of KEAP1 to activate NRF2 signaling. This study identifies KEAP1 as capable of sensing reactive metabolites not only by several cysteine residues but also by a conserved lysine residue, indicating its potential to sense an expanded repertoire of reactive metabolic messengers.
Identifiants
pubmed: 37619563
pii: S2451-9456(23)00243-X
doi: 10.1016/j.chembiol.2023.07.014
pmc: PMC10592117
mid: NIHMS1926729
pii:
doi:
Substances chimiques
Kelch-Like ECH-Associated Protein 1
0
NF-E2-Related Factor 2
0
Lysine
K3Z4F929H6
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Langues
eng
Sous-ensembles de citation
IM
Pagination
1295-1302.e4Subventions
Organisme : NIA NIH HHS
ID : R01 AG046495
Pays : United States
Organisme : NIDDK NIH HHS
ID : R01 DK107604
Pays : United States
Organisme : NIGMS NIH HHS
ID : R35 GM146865
Pays : United States
Organisme : NIA NIH HHS
ID : RF1 AG046495
Pays : United States
Commentaires et corrections
Type : UpdateOf
Informations de copyright
Copyright © 2023 Elsevier Ltd. All rights reserved.
Déclaration de conflit d'intérêts
Declaration of interests Declared none.
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