Sestrin 2 is a leucine sensor for the mTORC 1 pathway

Leucine is a proteogenic amino acid that also regulates many aspects of mammalian physiology, in large part by activating the mTOR complex 1 (mTORC1) protein kinase, a master growth controller. Amino acids signal to mTORC1 through the Rag guanine triphosphatases (GTPases). Several factors regulate the Rags, including GATOR1, a GTPase activating protein (GAP); GATOR2, a positive regulator of unknown function; and Sestrin2, a GATOR2-interacting protein that inhibits mTORC1 signaling. We find that leucine, but not arginine, disrupts the Sestrin2GATOR2 interaction by binding to Sestrin2 with a Kd of 20 μM, which is the leucine concentration that half-maximally activates mTORC1. The leucine-binding capacity of Sestrin2 is required for leucine to activate mTORC1 in cells. These results indicate that Sestrin2 is a leucine sensor for the mTORC1 pathway. It has long been appreciated that in addition to being a proteogenic amino acid, leucine is also a signaling molecule that directly regulates animal physiology, including satiety (1), insulin secretion (2), and skeletal muscle anabolism (3, 4). Because the liver has a low capacity to metabolize leucine, its blood concentrations fluctuate in accord with its consumption so that dietary leucine can directly impact physiology (5–7). A key mediator of the effects of leucine is the mTORC1 protein kinase (8, 9), which regulates growth by controlling processes like protein and lipid synthesis as well as autophagy. Many environmental signals besides leucine regulate the mTORC1 pathway, including other amino acids like arginine, as well as glucose and various growth factors and forms of stress Correspondence should be addressed to D.M.S. Tel: 617-258-6407; Fax: 617-452-3566; sabatini@wi.mit.edu. *These authors contributed equally to this work SUPPLEMENTARY MATERIALS: Materials and Methods Figures S1-S4 HHS Public Access Author manuscript Science. Author manuscript; available in PMC 2016 January 01. Published in final edited form as: Science. 2016 January 1; 351(6268): 43–48. doi:10.1126/science.aab2674. A uhor M anscript