ArfGAP1 inhibits mTORC1 lysosomal localization and activation

• Published in: The EMBO journal 2021-06, Vol.40 (12), p.e106412-n/a
• Main Authors: Meng, Delong, Yang, Qianmei, Melick, Chase H, Park, Brenden C, Hsieh, Ting‐Sung, Curukovic, Adna, Jeong, Mi‐Hyeon, Zhang, Junmei, James, Nicholas G, Jewell, Jenna L
• Format: Article
• Language: English
• Subjects: Adenosine diphosphate; Amino acids; Animals; ArfGAP1; Cancer; Cell growth; Cell Line; Chemoreception; Curvature; Deactivation; Depletion; EMBO20; EMBO21; Energy balance; Female; Growth factors; GTPase-Activating Proteins - genetics; GTPase-Activating Proteins - metabolism; Humans; Kaplan-Meier Estimate; Lipids; Localization; lysosome; Lysosomes; Lysosomes - metabolism; Male; Mathematical analysis; Mechanistic Target of Rapamycin Complex 1 - genetics; Mechanistic Target of Rapamycin Complex 1 - metabolism; Membranes; Mice; mTORC1; Nutrients; Pancreatic cancer; Pancreatic Neoplasms - genetics; Pancreatic Neoplasms - metabolism; Pancreatic Neoplasms - mortality; Prognosis; Proteins; Rapamycin; Ribosylation; TOR protein; vesicle trafficking
• ISSN: 0261-4189; 1460-2075
• DOI: 10.15252/embj.2020106412

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. SYNOPSIS Amino acids promote lysosomal localization and subsequent activation of the signaling integrator mTORC1. Here, mTORC1 recruitment to lysosomes is found to be actively prevented in the absence of amino acids via the newly identified interactor ArfGAP1. ArfGAP1 directly interacts with mTORC1 under amino acid‐depleted conditions. High levels of ArfGAP1 inhibit mTORC1 lysosomal localization and activation. Depletion of ArfGAP1 prevents mTORC1 lysosomal dissociation and deactivation upon amino acid withdrawal. Membrane curvature sensing motifs that mediate ArfGAP1 vesicle binding are crucial in the regulation of mTORC1. ArfGAP1 expression is prognostic of favorable clinical outcome for pancreatic cancer patients. Graphical Abstract ArfGAP1 represses cell growth and mTORC1 lysosomal recruitment independently of its GTPase‐activating function.