The mechanistic target of rapamycin (mTOR) signals through the mTOR complex 1 (mTORC1) and the mTOR complex 2 to maintain cellular and organismal homeostasis. Failure to finely tune mTOR activity results in metabolic dysregulation and disease. While there is substantial understanding of the molecular events leading mTORC1 activation at the lysosome, remarkably little is known about what terminates mTORC1 signaling. Here, we show that the AAA + ATPase Thorase directly binds mTOR, thereby orchestrating the disassembly and inactivation of mTORC1. Thorase disrupts the association of mTOR to Raptor at the mitochondria-lysosome interface and this action is sensitive to amino acids. Lack of Thorase causes accumulation of mTOR-Raptor complexes and altered mTORC1 disassembly/re-assembly dynamics upon changes in amino acid availability. The resulting excessive mTORC1 can be counteracted with rapamycin in vitro and in vivo. Collectively, we reveal Thorase as a key component of the mTOR pathway that disassembles and thus inhibits mTORC1.

雷帕霉素 (mTOR) 的机制靶点通过 mTOR 复合物 1 (mTORC1) 和 mTOR 复合物 2 发出信号以维持细胞和有机体稳态。未能精细调节 mTOR 活性会导致代谢失调和疾病。虽然人们对导致 mTORC1 在溶酶体激活的分子事件有了深入的了解，但对于终止 mTORC1 信号传导的因素却知之甚少。在这里，我们证明 AAA + ATPase Thorase 直接结合 mTOR，从而协调 mTORC1 的分解和失活。Thorase 会破坏线粒体-溶酶体界面处 mTOR 与 Raptor 的结合，并且这种作用对氨基酸敏感。Thorase 的缺乏会导致 mTOR-Raptor 复合物的积累，并在氨基酸可用性变化时改变 mTORC1 分解/重新组装动态。由此产生的过量 mTORC1 可以在体外和体内用雷帕霉素抵消。总的来说，我们揭示了 Thorase 是 mTOR 通路的关键组成部分，它可以分解并从而抑制 mTORC1。