Artículo
Succinate dehydrogenase/complex II is critical for metabolic and epigenetic regulation of T cell proliferation and inflammation
Autor/es | Chen, Xuyong
Sunkel, Benjamin Wang, Meng Kang, Siwen Wang, Tingting Gnanaprakasam, J N Rashida Muñoz Cabello, Ana María López Barneo, José Wang, Ruoning |
Departamento | Universidad de Sevilla. Fisiología Médica y Biofísica |
Fecha de publicación | 2022 |
Fecha de depósito | 2024-01-09 |
Publicado en |
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Resumen | Effective T cell-mediated immune responses require the proper allocation of metabolic resources to sustain growth, proliferation, and cytokine production. Epigenetic control of the genome also governs T cell transcriptome ... Effective T cell-mediated immune responses require the proper allocation of metabolic resources to sustain growth, proliferation, and cytokine production. Epigenetic control of the genome also governs T cell transcriptome and T cell lineage commitment and maintenance. Cellular metabolic programs interact with epigenetic regulation by providing substrates for covalent modifications of chromatin. By using complementary genetic, epigenetic, and metabolic approaches, we revealed that tricarboxylic acid (TCA) cycle flux fueled biosynthetic processes while controlling the ratio of succinate/α-ketoglutarate (α-KG) to modulate the activities of dioxygenases that are critical for driving T cell inflammation. In contrast to cancer cells, where succinate dehydrogenase (SDH)/complex II inactivation drives cell transformation and growth, SDH/complex II deficiency in T cells caused proliferation and survival defects when the TCA cycle was truncated, blocking carbon flux to support nucleoside biosynthesis. Replenishing the intracellular nucleoside pool partially relieved the dependence of T cells on SDH/complex II for proliferation and survival. SDH deficiency induced a proinflammatory gene signature in T cells and promoted T helper 1 and T helper 17 lineage differentiation. An increasing succinate/α-KG ratio in SDH-deficient T cells promoted inflammation by changing the pattern of the transcriptional and chromatin accessibility signatures and consequentially increasing the expression of the transcription factor, PR domain zinc finger protein 1. Collectively, our studies revealed a role of SDH/complex II in allocating carbon resources for anabolic processes and epigenetic regulation in T cell proliferation and inflammation. |
Agencias financiadoras | National Institute of Health (Cancer Moonshot program) United States Department of Health & Human Services National Institutes of Health (NIH) - USA V-Foundation V2014-001 American Cancer Society SBP NCI Cancer Center Support Grant Markey Cancer Center Support Grant |
Identificador del proyecto | 1UO1CA232488-01
2R01AI114581-06 RO1CA247941 V2014-001 128436-RSG-15-180-01-LIB P30 CA030199 P30CA177558 |
Cita | Chen, X., Sunkel, B., Wang, M., Kang, S., Wang, T., Gnanaprakasam, J.N.R.,...,Wang, R. (2022). Succinate dehydrogenase/complex II is critical for metabolic and epigenetic regulation of T cell proliferation and inflammation. Science immunology, 7 (70), eabm8161. https://doi.org/10.1126/sciimmunol.abm8161. |
Ficheros | Tamaño | Formato | Ver | Descripción |
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PMC9332111_Sci Immunol 1.pdf | 3.663Mb | [PDF] | Ver/ | |
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