mTORC1 通过一种需要液泡 H(+)-ATP 酶的内外机制感知溶酶体氨基酸。
mTORC1 senses lysosomal amino acids through an inside-out mechanism that requires the vacuolar H(+)-ATPase.
机构信息
Whitehead Institute for Biomedical Research, Nine Cambridge Center, Cambridge, MA 02142, USA.
出版信息
Science. 2011 Nov 4;334(6056):678-83. doi: 10.1126/science.1207056.
The mTOR complex 1 (mTORC1) protein kinase is a master growth regulator that is stimulated by amino acids. Amino acids activate the Rag guanosine triphosphatases (GTPases), which promote the translocation of mTORC1 to the lysosomal surface, the site of mTORC1 activation. We found that the vacuolar H(+)-adenosine triphosphatase ATPase (v-ATPase) is necessary for amino acids to activate mTORC1. The v-ATPase engages in extensive amino acid-sensitive interactions with the Ragulator, a scaffolding complex that anchors the Rag GTPases to the lysosome. In a cell-free system, ATP hydrolysis by the v-ATPase was necessary for amino acids to regulate the v-ATPase-Ragulator interaction and promote mTORC1 translocation. Results obtained in vitro and in human cells suggest that amino acid signaling begins within the lysosomal lumen. These results identify the v-ATPase as a component of the mTOR pathway and delineate a lysosome-associated machinery for amino acid sensing.
mTOR 复合物 1（mTORC1）蛋白激酶是一种主调控生长的激酶，受氨基酸刺激。氨基酸激活 Rag 鸟苷三磷酸酶（GTPase），促进 mTORC1 易位到溶酶体表面，即 mTORC1 激活的部位。我们发现液泡 H(+)-三磷酸腺苷酶（v-ATPase）对于氨基酸激活 mTORC1 是必需的。v-ATPase 与 Ragulator 进行广泛的氨基酸敏感相互作用，Ragulator 是一种支架复合物，将 Rag GTPase 锚定到溶酶体上。在无细胞体系中，v-ATPase 的 ATP 水解对于氨基酸调节 v-ATPase-Ragulator 相互作用和促进 mTORC1 易位是必需的。在体外和人细胞中获得的结果表明，氨基酸信号从溶酶体腔开始。这些结果将 v-ATPase 鉴定为 mTOR 途径的一个组成部分，并描绘了溶酶体相关的氨基酸感应机制。
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