Cutting Edge: TCR Signal Strength Regulates Acetyl-CoA Metabolism via AKT
Cutting Edge: TCR Signal Strength Regulates Acetyl-CoA Metabolism via AKT
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DOI：
10.4049/jimmunol.1900749
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发表时间：
2019-12-01
影响因子：
4.4
通讯作者：
Wendell, Stacy G.
中科院分区：
文献类型：
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作者：
Hawse, William F.;Cattley, Richard T.;Wendell, Stacy G.
TCR信号激活包括AKT/mTOR在内的与代谢网络相结合的激酶，以支持T细胞在免疫反应中的能量需求。人们认识到，CD4(+)T细胞亚群有不同的代谢需求。然而，TCR信号如何与中间代谢物的调节相结合，以及代谢物通量的变化如何有助于T细胞分化的研究较少。我们发现TCR信号通过AKT调节小鼠CD4(+)T细胞的乙酰辅酶A代谢。微弱的TCR信号促进AKT催化的柠檬酸合成酶的磷酸化和抑制、乙酰辅酶A水平的升高和线粒体蛋白质的高乙酰化。柠檬酸合成酶的基因敲除促进了核乙酰辅酶A水平的增加，增加了FOXP3启动子上的组蛋白乙酰化，并诱导了FOXP3转录。这些数据确定了AKT信号和乙酰辅酶A代谢之间的电路，通过TCR信号强度调节，乙酰辅酶A水平的瞬时波动在T细胞命运决定中发挥作用。
TCR signaling activates kinases including AKT/mTOR that engage metabolic networks to support the energetic demands of a T cell during an immune response. It is realized that CD4(+) T cell subsets have different metabolic requirements. Yet, how TCR signaling is coupled to the regulation of intermediate metabolites and how changes in metabolite flux contribute to T cell differentiation are less established. We find that TCR signaling regulates acetyl-CoA metabolism via AKT in murine CD4(+) T cells. Weak TCR signals promote AKT-catalyzed phosphorylation and inhibition of citrate synthase, elevated acetyl-CoA levels, and hyperace-tylation of mitochondrial proteins. Genetic knockdown of citrate synthase promotes increased nuclear acetylCoA levels, increased histone acetylation at the FOXP3 promotor and induction of FOXP3 transcription. These data identify a circuit between AKT signaling and acetyl-CoA metabolism regulated via TCR signal strength and that transient fluctuations in acetyl-CoA levels function in T cell fate decisions.