ArfGAP1 inhibits mTORC1 lysosomal localization and activation.
ArfGAP1 inhibits mTORC1 lysosomal localization and activation.
复制标题
DOI：
10.15252/embj.2020106412
复制
发表时间：
2021-06-15
期刊：
影响因子：
--
通讯作者：
Jewell JL
中科院分区：
文献类型：
--
作者：
Meng D;Yang Q;Melick CH;Park BC;Hsieh TS;Curukovic A;Jeong MH;Zhang J;James NG;Jewell JL
哺乳动物雷帕霉素靶蛋白复合物1（mTORC 1）整合营养素、生长因子、应激和能量状态来调节细胞生长和代谢。氨基酸促进mTORC 1溶酶体定位和随后的激活。然而，mTORC 1在氨基酸缺乏条件下的亚细胞位置或相互作用蛋白尚未完全了解。在这里，我们确定ADP-核糖基化因子GTP-激活蛋白1（ArfGAP 1）作为mTORC 1的关键调节因子。ArfGAP 1在不存在氨基酸的情况下与mTORC 1相互作用，并抑制mTORC 1溶酶体定位和活化。从机制上讲，与囊泡膜结合的膜曲率传感两亲性脂质包装传感器（ALPS）基序对于ArfGAP 1与mTORC 1相互作用并调节mTORC 1活性至关重要。重要的是，ArfGAP 1通过mTORC 1抑制细胞生长，并且是胰腺癌患者总生存期的独立预后因素。我们的研究确定ArfGAP 1是mTORC 1的关键调节因子，其通过阻止mTORC 1的溶酶体转运和激活来发挥作用，具有癌症治疗的潜力。ArfGAP 1抑制细胞生长和mTORC 1溶酶体募集，与其GTP酶激活功能无关。
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. ArfGAP1 represses cell growth and mTORC1 lysosomal recruitment independently of its GTPase‐activating function.