SNAT7 regulates mTORC1 via macropinocytosis.
Delong MengQianmei YangMi-Hyeon JeongAdna CurukovicShweta TiwaryChase H MelickTshering D Lama-SherpaHuanyu WangMariela Huerta-RosarioGreg UrquhartLauren G ZachariasCheryl M LewisRalph J DeBerardinisJenna L JewellPublished in: Proceedings of the National Academy of Sciences of the United States of America (2022)
Mammalian target of rapamycin complex 1 (mTORC1) senses amino acids to control cell growth, metabolism, and autophagy. Some amino acids signal to mTORC1 through the Rag GTPase, whereas glutamine and asparagine activate mTORC1 through a Rag GTPase-independent pathway. Here, we show that the lysosomal glutamine and asparagine transporter SNAT7 activates mTORC1 after extracellular protein, such as albumin, is macropinocytosed. The N terminus of SNAT7 forms nutrient-sensitive interaction with mTORC1 and regulates mTORC1 activation independently of the Rag GTPases. Depletion of SNAT7 inhibits albumin-induced mTORC1 lysosomal localization and subsequent activation. Moreover, SNAT7 is essential to sustain KRAS-driven pancreatic cancer cell growth through mTORC1. Thus, SNAT7 links glutamine and asparagine signaling from extracellular protein to mTORC1 independently of the Rag GTPases and is required for macropinocytosis-mediated mTORC1 activation and pancreatic cancer cell growth.