SNAT7 regulates mTORC1 via macropinocytosis
Delong Meng, Qianmei Yang, Mi‐Hyeon Jeong, Adna Curukovic, Shweta Tiwary, Chase H. Melick, Tshering Lama-Sherpa, Huanyu Wang, Mariela Huerta-Rosario, Greg Urquhart, Lauren G. Zacharias, Cheryl Lewis, Ralph J. DeBerardinis, Jenna L. Jewell
Abstract
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.