Parmigiani Anita, Nourbakhsh Aida, Ding Boxiao, Wang Wei, Kim Young Chul, Akopiants Konstantin, Guan Kun-Liang, Karin Michael, Budanov Andrei V
Cell Rep. 2014 Nov 20;9(4):1281-91. doi: 10.1016/j.celrep.2014.10.019.
The mechanistic target of rapamycin complex 1 (mTORC1) kinase is a sensor of different environmental conditions and regulator of cell growth, metabolism, and autophagy. mTORC1 is activated by Rag GTPases, working as RagA:RagB and RagC:RagD heterodimers. Rags control mTORC1 activity by tethering mTORC1 to the lysosomes where it is activated by Rheb GTPase. RagA:RagB, active in its GTP-bound form, is inhibited by GATOR1 complex, a GTPase-activating protein, and GATOR1 is in turn negatively regulated by GATOR2 complex. Sestrins are stress-responsive proteins that inhibit mTORC1 via activation of AMP-activated protein kinase (AMPK) and tuberous sclerosis complex. Here we report an AMPK-independent mechanism of mTORC1 inhibition by Sestrins mediated by their interaction with GATOR2. As a result of this interaction, the Sestrins suppress mTOR lysosomal localization in a Rag-dependent manner. This mechanism is potentially involved in mTORC1 regulation by amino acids, rotenone, and tunicamycin, connecting stress response with mTORC1 inhibition.
雷帕霉素复合物1（mTORC1）激酶是不同环境条件的传感器，也是细胞生长、代谢和自噬的调节因子。mTORC1由Rag GTP酶激活，以RagA:RagB和RagC:RagD异二聚体的形式发挥作用。Rags通过将mTORC1拴系到溶酶体上来控制mTORC1的活性，在溶酶体中mTORC1被Rheb GTP酶激活。以其GTP结合形式存在的活性RagA:RagB被GATOR1复合物（一种GTP酶激活蛋白）抑制，而GATOR1又受到GATOR2复合物的负调控。 sestrins是应激反应蛋白，通过激活AMP激活的蛋白激酶（AMPK）和结节性硬化复合物来抑制mTORC1。在这里，我们报告了一种sestrins通过与GATOR2相互作用介导的不依赖AMPK的mTORC1抑制机制。这种相互作用的结果是，sestrins以Rag依赖的方式抑制mTOR的溶酶体定位。该机制可能参与了氨基酸、鱼藤酮和衣霉素对mTORC1的调节，将应激反应与mTORC1抑制联系起来。
