2. Academic Validation
  3. The glucose transporter GLUT3 controls T helper 17 cell responses through glycolytic-epigenetic reprogramming

The glucose transporter GLUT3 controls T helper 17 cell responses through glycolytic-epigenetic reprogramming

  • Cell Metab. 2022 Apr 5;34(4):516-532.e11. doi: 10.1016/j.cmet.2022.02.015.
Sophia M Hochrein 1,  Hao Wu 1,  Miriam Eckstein 1,  Laura Arrigoni 2,  Josip S Herman 3,  Fabian Schumacher 4,  Christian Gerecke 4,  Mathias Rosenfeldt 5,  Dominic Grün 3,  Burkhard Kleuser 4,  Georg Gasteiger 1,  Wolfgang Kastenmüller 1,  Bart Ghesquière 6,  Jan Van den Bossche 7,  E Dale Abel 8,  Martin Vaeth 9
Affiliations

Affiliations

  • 1 Würzburg Institute of Systems Immunology, Max Planck Research Group at the Julius-Maximilians University of Würzburg, Würzburg, Germany.
  • 2 Max Planck Institute of Immunobiology and Epigenetics, Freiburg, Germany.
  • 3 Würzburg Institute of Systems Immunology, Max Planck Research Group at the Julius-Maximilians University of Würzburg, Würzburg, Germany; Max Planck Institute of Immunobiology and Epigenetics, Freiburg, Germany.
  • 4 Institute of Pharmacy, Department of Pharmacology and Toxicology, Freie Universität Berlin, Berlin, Germany.
  • 5 Institute of Pathology, Julius-Maximilians University of Würzburg, Würzburg, Germany.
  • 6 Metabolomics Expertise Center, Department of Oncology, Katholieke Universiteit Leuven, Leuven, Belgium.
  • 7 Department of Molecular Cell Biology and Immunology, Amsterdam Cardiovascular Sciences, Amsterdam Institute for Infection and Immunity, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam, the Netherlands.
  • 8 Fraternal Order of Eagles Diabetes Research Center and Division of Endocrinology and Metabolism, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, IA, USA.
  • 9 Würzburg Institute of Systems Immunology, Max Planck Research Group at the Julius-Maximilians University of Würzburg, Würzburg, Germany. Electronic address: [email protected].
PMID: 35316657 DOI: 10.1016/j.cmet.2022.02.015
Abstract

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.

Keywords

ACLY; ATP-citrate lyase; GLUT1; GLUT3; Th17 cells; acetyl-CoA; glucose metabolism; glycolysis; histone acetylation; immunometabolism.

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