Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, Texas 75390; Harold C. Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, Texas 75390; Hamon Center for Regenerative Science and Medicine, University of Texas Southwestern Medical Center, Dallas, Texas 75390.
Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, Texas 75390; Harold C. Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, Texas 75390; Hamon Center for Regenerative Science and Medicine, University of Texas Southwestern Medical Center, Dallas, Texas 75390.
J Biol Chem. 2020 Mar 6;295(10):2890-2899. doi: 10.1074/jbc.AC119.011578. Epub 2020 Feb 4.
Nutrient sensing by cells is crucial, and when this sensing mechanism is disturbed, human disease can occur. mTOR complex 1 (mTORC1) senses amino acids to control cell growth, metabolism, and autophagy. Leucine, arginine, and methionine signal to mTORC1 through the well-characterized Rag GTPase signaling pathway. In contrast, glutamine activates mTORC1 through a Rag GTPase-independent mechanism that requires ADP-ribosylation factor 1 (Arf1). Here, using several biochemical and genetic approaches, we show that eight amino acids filter through the Rag GTPase pathway. Like glutamine, asparagine signals to mTORC1 through Arf1 in the absence of the Rag GTPases. Both the Rag-dependent and Rag-independent pathways required the lysosome and lysosomal function for mTORC1 activation. Our results show that mTORC1 is differentially regulated by amino acids through two distinct pathways.
细胞对营养物质的感知至关重要，而当这种感知机制受到干扰时，人类疾病就可能发生。mTOR 复合物 1（mTORC1）通过 Rag GTPase 信号通路感知氨基酸，以控制细胞生长、代谢和自噬。亮氨酸、精氨酸和蛋氨酸通过已充分研究的 Rag GTPase 信号通路向 mTORC1 发出信号。相比之下，谷氨酰胺通过 Rag GTPase 独立机制激活 mTORC1，该机制需要 ADP-核糖基化因子 1（Arf1）。在这里，我们使用几种生化和遗传方法表明，八种氨基酸通过 Rag GTPase 途径过滤。与谷氨酰胺一样，天冬酰胺通过 Arf1 向 mTORC1 发出信号，而无需 Rag GTPases。Rag 依赖性和 Rag 非依赖性途径都需要溶酶体和溶酶体功能来激活 mTORC1。我们的研究结果表明，mTORC1 通过两种不同的途径被氨基酸差异调节。
