Cytosolic Branched Chain Aminotransferase (BCATc) Regulates mTORC1 Signaling and Glycolytic Metabolism in CD4+ T Cells
Cytosolic Branched Chain Aminotransferase (BCATc) Regulates mTORC1 Signaling and Glycolytic Metabolism in CD4+ T Cells
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DOI：
10.1074/jbc.m114.554113
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发表时间：
2014-07-11
影响因子：
4.8
通讯作者：
Hutson, Susan M.
中科院分区：
文献类型：
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作者：
Ananieva, Elitsa A.;Patel, Chirag H.;Hutson, Susan M.
在这里，我们表明，胞质支链氨基转移酶（BCATc）的表达是由CD 4（+）T细胞的T细胞受体（TCR）触发的。BCATc的诱导与Leu转氨作用的增加相关，而来自BCATc（-/-）小鼠的T细胞表现出比来自野生型（WT）小鼠的细胞更低的Leu转氨作用和更高的细胞内Leu浓度。WT细胞中TCR对BCATc的诱导被活化T细胞的钙调神经磷酸酶核因子（NFAT）抑制剂环孢菌素A（CsA）阻止，表明NFAT控制BCATc表达。Leu是雷帕霉素复合物1（mTORC 1）的哺乳动物靶蛋白的已知激活剂。mTOR正在成为T细胞活化、分化和代谢的关键调节剂。来自BCATc（-/-）小鼠的活化T细胞显示mTORC 1下游靶标S6和4 EBP-1的磷酸化增加，表明mTORC 1活化高于来自WT小鼠的T细胞。此外，与活化的WT细胞相比，来自BCATc（-/-）小鼠的T细胞显示出更高的糖酵解速率、糖酵解能力和糖酵解储备。这些发现揭示了BCATc作为T细胞活化和代谢的新型调节剂，并突出了Leu代谢在T细胞中的重要作用。
Here we show that expression of the cytosolic branched chain aminotransferase (BCATc) is triggered by the T cell receptor (TCR) of CD4(+) T cells. Induction of BCATc correlates with increased Leu transamination, whereas T cells from the BCATc(-/-) mouse exhibit lower Leu transamination and higher intracellular Leu concentrations than the cells from wild type (WT) mice. Induction of BCATc by TCR in WT cells is prevented by the calcineurin-nuclear factor of activated T cells (NFAT) inhibitor, cyclosporin A (CsA), suggesting that NFAT controls BCATc expression. Leu is a known activator of the mammalian target of rapamycin complex 1 (mTORC1). mTOR is emerging as a critical regulator of T cell activation, differentiation, and metabolism. Activated T cells from BCATc(-/-) mice show increased phosphorylation of mTORC1 downstream targets, S6 and 4EBP-1, indicating higher mTORC1 activation than in T cells from WT mice. Furthermore, T cells from BCATc(-/-) mice display higher rates of glycolysis, glycolytic capacity, and glycolytic reserve when compared with activated WT cells. These findings reveal BCATc as a novel regulator of T cell activation and metabolism and highlight the important role of Leu metabolism in T cells.