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Pyruvate metabolism controls chromatin remodeling during CD4+ T cell activation.
Mocholi, Enric; Russo, Laura; Gopal, Keshav; Ramstead, Andrew G; Hochrein, Sophia M; Vos, Harmjan R; Geeven, Geert; Adegoke, Adeolu O; Hoekstra, Anna; van Es, Robert M; Pittol, Jose Ramos; Vastert, Sebastian; Rutter, Jared; Radstake, Timothy; van Loosdregt, Jorg; Berkers, Celia; Mokry, Michal; Anderson, Colin C; O'Connell, Ryan M; Vaeth, Martin; Ussher, John; Burgering, Boudewijn M T; Coffer, Paul J.
Afiliação
  • Mocholi E; 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.
  • Russo L; Center for Molecular Medicine, University Medical Center Utrecht, Utrecht, the Netherlands; Regenerative Medicine Center, University Medical Center Utrecht, Utrecht, the Netherlands.
  • Gopal K; Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, AB, Canada.
  • Ramstead AG; 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.
  • Hochrein SM; Würzburg Institute of Systems Immunology, Max Planck Research Group, Julius-Maximilians University of Würzburg, Würzburg, Germany.
  • Vos HR; Center for Molecular Medicine, University Medical Center Utrecht, Utrecht, the Netherlands.
  • Geeven G; Department of Clinical Genetics, Erasmus MC-University Medical Center, Rotterdam, the Netherlands.
  • Adegoke AO; Department of Surgery, University of Alberta, Edmonton, AB, Canada.
  • Hoekstra A; Biomolecular Mass Spectrometry and Proteomics, Bijvoet Center for Biomolecular Research, Utrecht University, Utrecht, the Netherlands.
  • van Es RM; Center for Molecular Medicine, University Medical Center Utrecht, Utrecht, the Netherlands.
  • Pittol JR; Center for Molecular Medicine, University Medical Center Utrecht, Utrecht, the Netherlands.
  • Vastert S; Laboratory for Translational Immunology and Department of Pediatric Rheumatology and Immunology, University Medical Center Utrecht, Utrecht, the Netherlands.
  • Rutter J; 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.
  • Radstake T; 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.
  • van Loosdregt J; Laboratory for Translational Immunology and Department of Pediatric Rheumatology and Immunology, University Medical Center Utrecht, Utrecht, the Netherlands.
  • Berkers C; 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.
  • Mokry M; Regenerative Medicine Center, University Medical Center Utrecht, Utrecht, the Netherlands; Cardiovascular Genetics, University Medical Center Utrecht, Utrecht, the Netherlands.
  • Anderson CC; Department of Surgery, University of Alberta, Edmonton, AB, Canada.
  • O'Connell RM; 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.
  • Vaeth M; Würzburg Institute of Systems Immunology, Max Planck Research Group, Julius-Maximilians University of Würzburg, Würzburg, Germany.
  • Ussher J; Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, AB, Canada.
  • Burgering BMT; Center for Molecular Medicine, University Medical Center Utrecht, Utrecht, the Netherlands.
  • Coffer PJ; 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.
Cell Rep ; 42(6): 112583, 2023 06 27.
Article em En | MEDLINE | ID: mdl-37267106
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.
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Histonas / Montagem e Desmontagem da Cromatina Limite: Humans Idioma: En Revista: Cell Rep Ano de publicação: 2023 Tipo de documento: Article

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Histonas / Montagem e Desmontagem da Cromatina Limite: Humans Idioma: En Revista: Cell Rep Ano de publicação: 2023 Tipo de documento: Article