Cell Reports (Jun 2023)
Pyruvate metabolism controls chromatin remodeling during CD4+ T cell activation
- Enric Mocholi,
- Laura Russo,
- Keshav Gopal,
- Andrew G. Ramstead,
- Sophia M. Hochrein,
- Harmjan R. Vos,
- Geert Geeven,
- Adeolu O. Adegoke,
- Anna Hoekstra,
- Robert M. van Es,
- Jose Ramos Pittol,
- Sebastian Vastert,
- Jared Rutter,
- Timothy Radstake,
- Jorg van Loosdregt,
- Celia Berkers,
- Michal Mokry,
- Colin C. Anderson,
- Ryan M. O’Connell,
- Martin Vaeth,
- John Ussher,
- Boudewijn M.T. Burgering,
- Paul J. Coffer
Affiliations
- Enric Mocholi
- Center for Molecular Medicine, University Medical Center Utrecht, Utrecht, the Netherlands; Regenerative Medicine Center, University Medical Center Utrecht, Utrecht, the Netherlands; Corresponding author
- Laura Russo
- Center for Molecular Medicine, University Medical Center Utrecht, Utrecht, the Netherlands; Regenerative Medicine Center, University Medical Center Utrecht, Utrecht, the Netherlands
- Keshav Gopal
- Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, AB, Canada
- Andrew G. Ramstead
- 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
- Sophia M. Hochrein
- Würzburg Institute of Systems Immunology, Max Planck Research Group, Julius-Maximilians University of Würzburg, Würzburg, Germany
- Harmjan R. Vos
- Center for Molecular Medicine, University Medical Center Utrecht, Utrecht, the Netherlands
- Geert Geeven
- Department of Clinical Genetics, Erasmus MC-University Medical Center, Rotterdam, the Netherlands
- Adeolu O. Adegoke
- Department of Surgery, University of Alberta, Edmonton, AB, Canada
- Anna Hoekstra
- Biomolecular Mass Spectrometry and Proteomics, Bijvoet Center for Biomolecular Research, Utrecht University, Utrecht, the Netherlands
- Robert M. van Es
- Center for Molecular Medicine, University Medical Center Utrecht, Utrecht, the Netherlands
- Jose Ramos Pittol
- Center for Molecular Medicine, University Medical Center Utrecht, Utrecht, the Netherlands
- Sebastian Vastert
- Laboratory for Translational Immunology and Department of Pediatric Rheumatology and Immunology, University Medical Center Utrecht, Utrecht, the Netherlands
- Jared Rutter
- 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
- Timothy Radstake
- 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
- Jorg van Loosdregt
- Laboratory for Translational Immunology and Department of Pediatric Rheumatology and Immunology, University Medical Center Utrecht, Utrecht, the Netherlands
- Celia Berkers
- 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
- Michal Mokry
- Regenerative Medicine Center, University Medical Center Utrecht, Utrecht, the Netherlands; Cardiovascular Genetics, University Medical Center Utrecht, Utrecht, the Netherlands
- Colin C. Anderson
- Department of Surgery, University of Alberta, Edmonton, AB, Canada
- Ryan M. O’Connell
- 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
- Martin Vaeth
- Würzburg Institute of Systems Immunology, Max Planck Research Group, Julius-Maximilians University of Würzburg, Würzburg, Germany
- John Ussher
- Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, AB, Canada
- Boudewijn M.T. Burgering
- Center for Molecular Medicine, University Medical Center Utrecht, Utrecht, the Netherlands
- Paul J. Coffer
- Center for Molecular Medicine, University Medical Center Utrecht, Utrecht, the Netherlands; Regenerative Medicine Center, University Medical Center Utrecht, Utrecht, the Netherlands; Corresponding author
- Journal volume & issue
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Vol. 42,
no. 6
p. 112583
Abstract
Summary: 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.
