2. Academic Validation
  3. Pyruvate metabolism controls chromatin remodeling during CD4+ T cell activation

Pyruvate metabolism controls chromatin remodeling during CD4+ T cell activation

  • Cell Rep. 2023 Jun 1;42(6):112583. doi: 10.1016/j.celrep.2023.112583.
Enric Mocholi 1,  Laura Russo 2,  Keshav Gopal 3,  Andrew G Ramstead 4,  Sophia M Hochrein 5,  Harmjan R Vos 6,  Geert Geeven 7,  Adeolu O Adegoke 8,  Anna Hoekstra 9,  Robert M van Es 6,  Jose Ramos Pittol 6,  Sebastian Vastert 10,  Jared Rutter 4,  Timothy Radstake 11,  Jorg van Loosdregt 10,  Celia Berkers 12,  Michal Mokry 13,  Colin C Anderson 8,  Ryan M O'Connell 4,  Martin Vaeth 5,  John Ussher 3,  Boudewijn M T Burgering 6,  Paul J Coffer 14
Affiliations

Affiliations

  • 1 Center for Molecular Medicine, University Medical Center Utrecht, Utrecht, the Netherlands; Regenerative Medicine Center, University Medical Center Utrecht, Utrecht, the Netherlands. Electronic address: e.mocholi-gimeno@umcutrecht.nl.
  • 2 Center for Molecular Medicine, University Medical Center Utrecht, Utrecht, the Netherlands; Regenerative Medicine Center, University Medical Center Utrecht, Utrecht, the Netherlands.
  • 3 Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, AB, Canada.
  • 4 Huntsman Cancer Institute and Division of Microbiology and Immunology, Department of Pathology, University of Utah, 15 N. Medical Drive East, Salt Lake City, UT, USA.
  • 5 Würzburg Institute of Systems Immunology, Max Planck Research Group, Julius-Maximilians University of Würzburg, Würzburg, Germany.
  • 6 Center for Molecular Medicine, University Medical Center Utrecht, Utrecht, the Netherlands.
  • 7 Department of Clinical Genetics, Erasmus MC-University Medical Center, Rotterdam, the Netherlands.
  • 8 Department of Surgery, University of Alberta, Edmonton, AB, Canada.
  • 9 Biomolecular Mass Spectrometry and Proteomics, Bijvoet Center for Biomolecular Research, Utrecht University, Utrecht, the Netherlands.
  • 10 Laboratory for Translational Immunology and Department of Pediatric Rheumatology and Immunology, University Medical Center Utrecht, Utrecht, the Netherlands.
  • 11 Laboratory for Translational Immunology and Department of Pediatric Rheumatology and Immunology, University Medical Center Utrecht, Utrecht, the Netherlands; Department of Rheumatology and Clinical Immunology, University Medical Center Utrecht, Utrecht, the Netherlands.
  • 12 Biomolecular Mass Spectrometry and Proteomics, Bijvoet Center for Biomolecular Research, Utrecht University, Utrecht, the Netherlands; Department of Biochemistry and Cell Biology, Faculty of Veterinary Medicine, Utrecht University, Utrecht, the Netherlands.
  • 13 Regenerative Medicine Center, University Medical Center Utrecht, Utrecht, the Netherlands; Cardiovascular Genetics, University Medical Center Utrecht, Utrecht, the Netherlands.
  • 14 Center for Molecular Medicine, University Medical Center Utrecht, Utrecht, the Netherlands; Regenerative Medicine Center, University Medical Center Utrecht, Utrecht, the Netherlands. Electronic address: p.j.coffer@umcutrecht.nl.
PMID: 37267106 DOI: 10.1016/j.celrep.2023.112583
Abstract

Upon antigen-specific T cell receptor (TCR) engagement, human CD4+ T cells proliferate and differentiate, a process associated with rapid transcriptional changes and metabolic reprogramming. Here, we show that the generation of extramitochondrial pyruvate is an important step for acetyl-CoA production and subsequent H3K27ac-mediated remodeling of histone acetylation. Histone modification, transcriptomic, and carbon tracing analyses of pyruvate dehydrogenase (PDH)-deficient T cells show PDH-dependent acetyl-CoA generation as a rate-limiting step during T activation. Furthermore, T cell activation results in the nuclear translocation of PDH and its association with both the p300 acetyltransferase and histone H3K27ac. These data support the tight integration of metabolic and histone-modifying enzymes, allowing metabolic reprogramming to fuel CD4+ T cell activation. Targeting this pathway may provide a therapeutic approach to specifically regulate antigen-driven T cell activation.

Keywords

CP: Metabolism; T cell; citrate; epigenetics; epigenome remodeling; glucose metabolism; glycolysis; histone acetylation; nuclear metabolism; pyruvate; pyruvate dehydrogenase.

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