Nutrient sensing by the mTOR complex 1 (mTORC1) requires its translocation to the lysosomal membrane. Upon amino acids removal, mTORC1 becomes cytosolic and inactive, yet its precise subcellular localization and the mechanism of inhibition remain elusive. Here, we identified Aster‐C as a negative regulator of mTORC1 signaling. Aster‐C earmarked a special rough ER subdomain where it sequestered mTOR together with the GATOR2 complex to prevent mTORC1 activation during nutrient starvation. Amino acids stimulated rapid disassociation of mTORC1 from Aster‐C concurrently with assembly of COP I vesicles which escorted mTORC1 to the lysosomal membrane. Consequently, ablation of Aster‐C led to spontaneous activation of mTORC1 and dissociation of TSC2 from lysosomes, whereas inhibition of COP I vesicle biogenesis or actin dynamics prevented mTORC1 activation. Together, these findings identified Aster‐C as a missing link between lysosomal trafficking and mTORC1 activation by revealing an unexpected role of COP I vesicles in mTORC1 signaling.

中文翻译：

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Aster-C 与 COP I 囊泡协同调节溶酶体运输和 mTORC1 的激活。

mTOR 复合体 1 (mTORC1) 的营养感应需要其易位到溶酶体膜。去除氨基酸后，mTORC1 变为细胞质且无活性，但其精确的亚细胞定位和抑制机制仍然难以捉摸。在这里，我们将 Aster-C 确定为 mTORC1 信号传导的负调节因子。Aster-C 指定了一个特殊的粗糙 ER 子域，它将 mTOR 与 GATOR2 复合物隔离在一起，以防止在营养饥饿期间激活 mTORC1。氨基酸刺激 mTORC1 从 Aster-C 快速解离，同时组装 COP I 囊泡，将 mTORC1 护送到溶酶体膜。因此，Aster-C 的消融导致 mTORC1 自发激活和 TSC2 从溶酶体解离，而抑制 COP I 囊泡生物发生或肌动蛋白动力学阻止了 mTORC1 激活。总之，这些发现通过揭示 COP I 囊泡在 mTORC1 信号传导中的意外作用，将 Aster-C 确定为溶酶体运输和 mTORC1 激活之间的缺失环节。