Sestrin2 is a leucine sensor for the mTORC1 pathway

• Published in: Science (American Association for the Advancement of Science) Vol. 351; no. 6268; pp. 43 - 48
• Main Authors: Wolfson, Rachel L., Chantranupong, Lynne, Saxton, Robert A., Shen, Kuang, Scaria, Sonia M., Cantor, Jason R., Sabatini, David M.
• Format: Journal Article
• Language: English
• Published: United States American Association for the Advancement of Science 01.01.2016; The American Association for the Advancement of Science
• Subjects: Amino acids; Cell growth; Government regulations; GTPase-Activating Proteins - metabolism; HEK293 Cells; Humans; Kinases; Leucine; Leucine - metabolism; Mechanistic Target of Rapamycin Complex 1; Metabolic Networks and Pathways; Metabolism; Multiprotein Complexes - metabolism; Nuclear Proteins - chemistry; Nuclear Proteins - genetics; Nuclear Proteins - metabolism; Pathways; Physiology; Protein Binding; Proteins; Proteins - chemistry; Proteins - metabolism; Sensors; Signal Transduction; TOR Serine-Threonine Kinases - metabolism
• ISSN: 0036-8075; 1095-9203
• DOI: 10.1126/science.aab2674

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 guanosine triphosphatases (GTPases). Several factors regulate the Rags, including GATOR1, a GTPase-activating protein; 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 Sestrin2-GATOR2 interaction by binding to Sestrin2 with a dissociation constant of 20 micromolar, 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.