Goodman Cancer Research Centre, McGill University, Montreal, QC H3A 1A3, Canada; Department of Biochemistry, McGill University, Montreal, QC H3A 1A3, Canada.
Centre for Systems Biology, Lunenfeld-Tanenbaum Research Institute, Sinai Health System, Toronto, ON M5G 1X5, Canada; Department of Molecular Genetics, University of Toronto, Toronto, ON M5S 1A1, Canada.
Mol Cell. 2021 Jan 21;81(2):398-407.e4. doi: 10.1016/j.molcel.2020.11.036. Epub 2020 Dec 18.
Mechanistic target of rapamycin complex 1 (mTORC1) controls cell growth and proliferation by sensing fluctuations in environmental cues such as nutrients, growth factors, and energy levels. The Rag GTPases (Rags) serve as a critical module that signals amino acid (AA) availability to modulate mTORC1 localization and activity. Recent studies have demonstrated how AAs regulate mTORC1 activity through Rags. Here, we uncover an unconventional pathway that activates mTORC1 in response to variations in threonine (Thr) levels via mitochondrial threonyl-tRNA synthetase TARS2. TARS2 interacts with inactive Rags, particularly GTP-RagC, leading to increased GTP loading of RagA. mTORC1 activity in cells lacking TARS2 is resistant to Thr repletion, showing that TARS2 is necessary for Thr-dependent mTORC1 activation. The requirement of TARS2, but not cytoplasmic threonyl-tRNA synthetase TARS, for this effect demonstrates an additional layer of complexity in the regulation of mTORC1 activity.
雷帕霉素复合物 1 （mTORC1）通过感知环境线索（如营养物质、生长因子和能量水平）的波动来控制细胞生长和增殖。Rag GTPases（Rags）作为一个关键模块，可通过信号传递氨基酸（AA）的可用性来调节 mTORC1 的定位和活性。最近的研究表明，AA 通过 Rag 调节 mTORC1 的活性。在这里，我们揭示了一种非传统途径，该途径通过线粒体苏氨酰-tRNA 合成酶 TARS2 响应苏氨酸（Thr）水平的变化来激活 mTORC1。TARS2 与无活性的 Rag 相互作用，特别是 GTP-RagC，导致 RagA 的 GTP 加载增加。缺乏 TARS2 的细胞中 mTORC1 的活性对 Thr 补充有抗性，表明 TARS2 是 Thr 依赖性 mTORC1 激活所必需的。TARS2 的需求，但不是细胞质苏氨酰-tRNA 合成酶 TARS 的需求，证明了 mTORC1 活性调节的另一个复杂性层次。
