Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, TX, USA.
Harold C. Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, TX, USA.
EMBO J. 2021 Jun 15;40(12):e106412. doi: 10.15252/embj.2020106412. Epub 2021 May 14.
The mammalian target of rapamycin complex 1 (mTORC1) integrates nutrients, growth factors, stress, and energy status to regulate cell growth and metabolism. Amino acids promote mTORC1 lysosomal localization and subsequent activation. However, the subcellular location or interacting proteins of mTORC1 under amino acid-deficient conditions is not completely understood. Here, we identify ADP-ribosylation factor GTPase-activating protein 1 (ArfGAP1) as a crucial regulator of mTORC1. ArfGAP1 interacts with mTORC1 in the absence of amino acids and inhibits mTORC1 lysosomal localization and activation. Mechanistically, the membrane curvature-sensing amphipathic lipid packing sensor (ALPS) motifs that bind to vesicle membranes are crucial for ArfGAP1 to interact with and regulate mTORC1 activity. Importantly, ArfGAP1 represses cell growth through mTORC1 and is an independent prognostic factor for the overall survival of pancreatic cancer patients. Our study identifies ArfGAP1 as a critical regulator of mTORC1 that functions by preventing the lysosomal transport and activation of mTORC1, with potential for cancer therapeutics.
哺乳动物雷帕霉素靶蛋白复合物 1（mTORC1）整合了营养物质、生长因子、应激和能量状态，以调节细胞生长和代谢。氨基酸促进 mTORC1 溶酶体定位和随后的激活。然而，在氨基酸缺乏条件下，mTORC1 的亚细胞位置或相互作用蛋白尚不完全清楚。在这里，我们确定 ADP-核糖基化因子 GTP 酶激活蛋白 1（ArfGAP1）是 mTORC1 的关键调节因子。在没有氨基酸的情况下，ArfGAP1 与 mTORC1 相互作用，并抑制 mTORC1 溶酶体定位和激活。在机制上，与囊泡膜结合的膜曲率感应两性脂质包装传感器（ALPS）基序对于 ArfGAP1 与 mTORC1 相互作用和调节 mTORC1 活性至关重要。重要的是，ArfGAP1 通过 mTORC1 抑制细胞生长，并且是胰腺导管腺癌患者总生存的独立预后因素。我们的研究确定 ArfGAP1 是 mTORC1 的关键调节因子，通过防止 mTORC1 的溶酶体运输和激活来发挥作用，具有癌症治疗的潜力。
