Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA.
Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA.
Nat Commun. 2022 Aug 17;13(1):4836. doi: 10.1038/s41467-022-32365-2.
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.
雷帕霉素的作用靶点（mTOR）通过 mTOR 复合物 1（mTORC1）和 mTOR 复合物 2 发出信号，以维持细胞和机体的内稳态。mTOR 活性不能精细调节会导致代谢失调和疾病。尽管人们对导致溶酶体中 mTORC1 激活的分子事件有了大量的了解，但对于终止 mTORC1 信号的机制却知之甚少。在这里，我们发现 AAA+ATP 酶 Thorase 直接与 mTOR 结合，从而协调 mTORC1 的解体和失活。Thorase 破坏了 mTOR 与 Raptor 在线粒体-溶酶体界面的结合，这一作用对氨基酸敏感。缺乏 Thorase 会导致 mTOR-Raptor 复合物的积累，并改变氨基酸可用性变化时 mTORC1 的解体/再组装动力学。体外和体内实验表明，这种过量的 mTORC1 可以用雷帕霉素来抵消。总的来说，我们揭示了 Thorase 作为 mTOR 通路的一个关键组成部分，它可以使 mTORC1 解体并抑制其活性。
