The dysregulation of the metabolic regulator TOR complex I (TORC1) contributes to a wide array of human pathologies. Tuberous sclerosis complex (TSC) is a potent inhibitor of TORC1. Here, we demonstrate that the Rag GTPase acts in both the amino-acid-sensing and growth factor signaling pathways to control TORC1 activity through the regulation of TSC dynamics in HeLa cells and Drosophila. We find that TSC lysosomal-cytosolic exchange increases in response to both amino acid and growth factor restriction. Moreover, the rate of exchange mirrors TSC function, with depletions of the Rag GTPase blocking TSC lysosomal mobility and rescuing TORC1 activity. Finally, we show that the GATOR2 complex controls the phosphorylation of TSC2, which is essential for TSC exchange. Our data support the model that the amino acid and growth factor signaling pathways converge on the Rag GTPase to inhibit TORC1 activity through the regulation of TSC dynamics.

代谢调节因子 TOR 复合物 I (TORC1) 的失调会导致多种人类病理。结节性硬化症复合体 (TSC) 是 TORC1 的有效抑制剂。在这里，我们证明 Rag GTPase 在氨基酸传感和生长因子信号通路中发挥作用，通过调节 HeLa 细胞和果蝇中的 TSC 动力学来控制 TORC1 活性。我们发现 TSC 溶酶体-胞质交换因氨基酸和生长因子限制而增加。此外，交换率反映了 TSC 的功能，Rag GTPase 的消耗会阻断 TSC 溶酶体的迁移性并挽救 TORC1 活性。最后，我们证明 GATOR2 复合物控制 TSC2 的磷酸化，这对于 TSC 交换至关重要。我们的数据支持这样的模型：氨基酸和生长因子信号通路汇聚在 Rag GTPase 上，通过调节 TSC 动力学来抑制 TORC1 活性。