The glucose transporter GLUT3 controls T helper 17 cell responses through glycolytic-epigenetic reprogramming.
ACLY
ATP-citrate lyase
GLUT1
GLUT3
Th17 cells
acetyl-CoA
glucose metabolism
glycolysis
histone acetylation
immunometabolism
Journal
Cell metabolism
ISSN: 1932-7420
Titre abrégé: Cell Metab
Pays: United States
ID NLM: 101233170
Informations de publication
Date de publication:
05 04 2022
05 04 2022
Historique:
received:
11
08
2021
revised:
04
01
2022
accepted:
23
02
2022
pubmed:
23
3
2022
medline:
9
4
2022
entrez:
22
3
2022
Statut:
ppublish
Résumé
Metabolic reprogramming is a hallmark of activated T cells. The switch from oxidative phosphorylation to aerobic glycolysis provides energy and intermediary metabolites for the biosynthesis of macromolecules to support clonal expansion and effector function. Here, we show that glycolytic reprogramming additionally controls inflammatory gene expression via epigenetic remodeling. We found that the glucose transporter GLUT3 is essential for the effector functions of Th17 cells in models of autoimmune colitis and encephalomyelitis. At the molecular level, we show that GLUT3-dependent glucose uptake controls a metabolic-transcriptional circuit that regulates the pathogenicity of Th17 cells. Metabolomic, epigenetic, and transcriptomic analyses linked GLUT3 to mitochondrial glucose oxidation and ACLY-dependent acetyl-CoA generation as a rate-limiting step in the epigenetic regulation of inflammatory gene expression. Our findings are also important from a translational perspective because inhibiting GLUT3-dependent acetyl-CoA generation is a promising metabolic checkpoint to mitigate Th17-cell-mediated inflammatory diseases.
Identifiants
pubmed: 35316657
pii: S1550-4131(22)00087-0
doi: 10.1016/j.cmet.2022.02.015
pmc: PMC9019065
mid: NIHMS1786644
pii:
doi:
Substances chimiques
Glucose Transport Proteins, Facilitative
0
Glucose Transporter Type 3
0
Acetyl Coenzyme A
72-89-9
ATP Citrate (pro-S)-Lyase
EC 2.3.3.8
Glucose
IY9XDZ35W2
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Research Support, N.I.H., Extramural
Langues
eng
Sous-ensembles de citation
IM
Pagination
516-532.e11Subventions
Organisme : NHLBI NIH HHS
ID : U54 HL112311
Pays : United States
Commentaires et corrections
Type : CommentIn
Informations de copyright
Copyright © 2022 Elsevier Inc. All rights reserved.
Déclaration de conflit d'intérêts
Declaration of interests The authors declare no competing interests.
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