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）的机械靶标通过感知环境线索（如营养素，生长因子和能量水平）的波动来控制细胞的生长和增殖。Rag GTPases（Rags）是一个重要模块，可向氨基酸（AA）发出信号，以调节mTORC1的定位和活性。最近的研究表明AA如何通过碎布调节mTORC1的活性。在这里，我们发现了一个非常规途径，该途径通过线粒体苏氨酸-tRNA合成酶TARS2响应于苏氨酸（Thr）水平的变化而激活mTORC1。TARS2与无效的Rags（尤其是GTP-RagC）相互作用，导致RagA的GTP负载增加。缺少TARS2的细胞中的mTORC1活性可抵抗Thr补充，表明TARS2对于Thr依赖的mTORC1激活是必需的。TARS2的要求，