Würzburg Institute of Systems Immunology, Max Planck Research Group at the Julius-Maximilians University of Würzburg, Würzburg, Germany.
Max Planck Institute of Immunobiology and Epigenetics, Freiburg, Germany.
Cell Metab. 2022 Apr 5;34(4):516-532.e11. doi: 10.1016/j.cmet.2022.02.015. Epub 2022 Mar 21.
Metabolic reprogramming is a hallmark of activated T cells. The switch from oxidative phosphorylation to aerobic glycolysis provides energy and intermediary metabolites for the biosynthesis of macromolecules to support clonal expansion and effector function. Here, we show that glycolytic reprogramming additionally controls inflammatory gene expression via epigenetic remodeling. We found that the glucose transporter GLUT3 is essential for the effector functions of Th17 cells in models of autoimmune colitis and encephalomyelitis. At the molecular level, we show that GLUT3-dependent glucose uptake controls a metabolic-transcriptional circuit that regulates the pathogenicity of Th17 cells. Metabolomic, epigenetic, and transcriptomic analyses linked GLUT3 to mitochondrial glucose oxidation and ACLY-dependent acetyl-CoA generation as a rate-limiting step in the epigenetic regulation of inflammatory gene expression. Our findings are also important from a translational perspective because inhibiting GLUT3-dependent acetyl-CoA generation is a promising metabolic checkpoint to mitigate Th17-cell-mediated inflammatory diseases.
代谢重编程是活化 T 细胞的一个标志。从氧化磷酸化到有氧糖酵解的转变为大分子的生物合成提供了能量和中间代谢物，以支持克隆扩增和效应功能。在这里，我们表明糖酵解重编程还通过表观遗传重塑来控制炎症基因表达。我们发现，葡萄糖转运蛋白 GLUT3 对于自身免疫性结肠炎和脑脊髓炎模型中 Th17 细胞的效应功能至关重要。在分子水平上，我们表明 GLUT3 依赖性葡萄糖摄取控制着一个代谢转录回路，该回路调节 Th17 细胞的致病性。代谢组学、表观遗传学和转录组学分析将 GLUT3 与线粒体葡萄糖氧化和 ACLY 依赖性乙酰辅酶 A 生成联系起来，作为炎症基因表达的表观遗传调控中的限速步骤。从转化的角度来看，我们的发现也很重要，因为抑制 GLUT3 依赖性乙酰辅酶 A 的产生是减轻 Th17 细胞介导的炎症性疾病的一个有前途的代谢检查点。
