ACLY and ACSS2 link nutrient-dependent chromatin accessibility to CD8 T cell effector responses.

Autor:	Kaymak I; Department of Metabolism and Nutritional Programming, Van Andel Institute, Grand Rapids, MI, USA., Watson MJ; Department of Metabolism and Nutritional Programming, Van Andel Institute, Grand Rapids, MI, USA., Oswald BM; Department of Metabolism and Nutritional Programming, Van Andel Institute, Grand Rapids, MI, USA., Ma S; NOMIS Center for Immunobiology and Microbial Pathogenesis, Salk Institute for Biological Studies , La Jolla, CA, USA., Johnson BK; Department of Epigenetics, Van Andel Institute, Grand Rapids, MI, USA.; Metabolism and Nutrition (MeNu) Program, Van Andel Institute , Grand Rapids, MI, USA., DeCamp LM; Department of Metabolism and Nutritional Programming, Van Andel Institute, Grand Rapids, MI, USA.; Metabolism and Nutrition (MeNu) Program, Van Andel Institute , Grand Rapids, MI, USA., Mabvakure BM; Department of Metabolism and Nutritional Programming, Van Andel Institute, Grand Rapids, MI, USA., Luda KM; Department of Metabolism and Nutritional Programming, Van Andel Institute, Grand Rapids, MI, USA.; Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen , København, Denmark., Ma EH; Department of Metabolism and Nutritional Programming, Van Andel Institute, Grand Rapids, MI, USA., Lau K; Bioinformatics and Biostatistics Core, Van Andel Institute , Grand Rapids, MI, USA., Fu Z; Bioinformatics and Biostatistics Core, Van Andel Institute , Grand Rapids, MI, USA., Muhire B; Department of Metabolism and Nutritional Programming, Van Andel Institute, Grand Rapids, MI, USA., Kitchen-Goosen SM; Department of Metabolism and Nutritional Programming, Van Andel Institute, Grand Rapids, MI, USA.; Metabolism and Nutrition (MeNu) Program, Van Andel Institute , Grand Rapids, MI, USA., Vander Ark A; Department of Metabolism and Nutritional Programming, Van Andel Institute, Grand Rapids, MI, USA., Dahabieh MS; Department of Metabolism and Nutritional Programming, Van Andel Institute, Grand Rapids, MI, USA., Samborska B; Goodman Cancer Institute, Faculty of Medicine, McGill University , Montréal, Canada., Vos M; Department of Metabolism and Nutritional Programming, Van Andel Institute, Grand Rapids, MI, USA.; Metabolism and Nutrition (MeNu) Program, Van Andel Institute , Grand Rapids, MI, USA., Shen H; Department of Epigenetics, Van Andel Institute, Grand Rapids, MI, USA., Fan ZP; Agios Pharmaceuticals , Cambridge, MA, USA., Roddy TP; Agios Pharmaceuticals , Cambridge, MA, USA., Kingsbury GA; Agios Pharmaceuticals , Cambridge, MA, USA., Sousa CM; Agios Pharmaceuticals , Cambridge, MA, USA., Krawczyk CM; Department of Metabolism and Nutritional Programming, Van Andel Institute, Grand Rapids, MI, USA.; Metabolism and Nutrition (MeNu) Program, Van Andel Institute , Grand Rapids, MI, USA., Williams KS; Department of Metabolism and Nutritional Programming, Van Andel Institute, Grand Rapids, MI, USA.; Metabolism and Nutrition (MeNu) Program, Van Andel Institute , Grand Rapids, MI, USA., Sheldon RD; Mass Spectrometry Core Facility, Van Andel Institute , Grand Rapids, MI, USA., Kaech SM; NOMIS Center for Immunobiology and Microbial Pathogenesis, Salk Institute for Biological Studies , La Jolla, CA, USA., Roy DG; Centre de Recherche du Centre Hospitalier de l'Université de Montréal , Montréal, Canada.; Département de Microbiologie, Infectiologie et Immunologie, Université de Montréal, Montréal, Canada.; Institut du Cancer de Montréal , Montréal, Canada., Jones RG; Department of Metabolism and Nutritional Programming, Van Andel Institute, Grand Rapids, MI, USA.; Metabolism and Nutrition (MeNu) Program, Van Andel Institute , Grand Rapids, MI, USA.
Jazyk:	angličtina
Zdroj:	The Journal of experimental medicine [J Exp Med] 2024 Sep 02; Vol. 221 (9). Date of Electronic Publication: 2024 Aug 16.
DOI:	10.1084/jem.20231820
Abstrakt:	Coordination of cellular metabolism is essential for optimal T cell responses. Here, we identify cytosolic acetyl-CoA production as an essential metabolic node for CD8 T cell function in vivo. We show that CD8 T cell responses to infection depend on acetyl-CoA derived from citrate via the enzyme ATP citrate lyase (ACLY). However, ablation of ACLY triggers an alternative, acetate-dependent pathway for acetyl-CoA production mediated by acyl-CoA synthetase short-chain family member 2 (ACSS2). Mechanistically, acetate fuels both the TCA cycle and cytosolic acetyl-CoA production, impacting T cell effector responses, acetate-dependent histone acetylation, and chromatin accessibility at effector gene loci. When ACLY is functional, ACSS2 is not required, suggesting acetate is not an obligate metabolic substrate for CD8 T cell function. However, loss of ACLY renders CD8 T cells dependent on acetate (via ACSS2) to maintain acetyl-CoA production and effector function. Together, ACLY and ACSS2 coordinate cytosolic acetyl-CoA production in CD8 T cells to maintain chromatin accessibility and T cell effector function. (© 2024 Kaymak et al.)
Databáze:	MEDLINE
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