Phospholipase D-dependent mTOR complex 1 (mTORC1) activation by glutamine
Phospholipase D-dependent mTOR complex 1 (mTORC1) activation by glutamine
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DOI：
10.1074/jbc.ra118.004972
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发表时间：
2018-10-19
影响因子：
4.8
通讯作者：
Foster, David A.
中科院分区：
文献类型：
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作者：
Bernfeld, Elyssa;Menon, Deepak;Foster, David A.
谷氨酰胺是维持细胞增殖所需的一种关键营养物质，有助于核苷酸、蛋白质和脂肪的合成。MTOR复合体1(MTORC1)是一种高度保守的蛋白质复合体，是一种营养感受器，传递从分解代谢到合成代谢的信号。虽然谷氨酰胺在mTORC1的激活中起着重要作用，但其机制尚不清楚。在这里，我们描述了谷氨酰胺激活mTORC1的亮氨酸和RAG非依赖性机制，该机制依赖于磷脂酶D和磷脂酸的产生，而磷脂酸是mTORC1稳定和活性所必需的。谷氨酰胺对mTORC1磷脂酶D依赖的激活依赖于GTP酶ADP核糖化因子1(Arf1)、Rala和Rheb。谷氨酰胺的下游代谢物-酮戊二酸可以挽救谷氨酰胺缺乏。这一机制代表了一种独立于RAG GTP酶和亮氨酸的对mTORC1的独特营养输入。
Glutamine is a key nutrient required for sustaining cell proliferation, contributing to nucleotide, protein, and lipid synthesis. The mTOR complex 1 (mTORC1) is a highly conserved protein complex that acts as a sensor of nutrients, relaying signals for the shift from catabolic to anabolic metabolism. Although glutamine plays an important role in mTORC1 activation, the mechanism is not clear. Here we describe a leucine- and Rag-independent mechanism of mTORC1 activation by glutamine that depends on phospholipase D and the production of phosphatidic acid, which is required for the stability and activity of mTORC1. The phospholipase D-dependent activation of mTORC1 by glutamine depended on the GTPases ADP ribosylation factor 1 (Arf1), RalA, and Rheb. Glutamine deprivation could be rescued by -ketoglutarate, a downstream metabolite of glutamine. This mechanism represents a distinct nutrient input to mTORC1 that is independent of Rag GTPases and leucine.