title: The Sestrins interact with GATOR2 to negatively regulate the amino-acid-sensing pathway upstream of mTORC1.
abstract: The mechanistic target of rapamycin complex 1 (mTORC1) kinase is a major regulator of cell growth that responds to numerous environmental cues. A key input is amino acids, which act through the heterodimeric Rag GTPases (RagA or RagB bound to RagC or RagD) in order to promote the translocation of mTORC1 to the lysosomal surface, its site of activation. GATOR2 is a complex of unknown function that positively regulates mTORC1 signaling by acting upstream of or in parallel to GATOR1, which is a GTPase-activating protein (GAP) for RagA or RagB and an inhibitor of the amino-acid-sensing pathway. Here, we find that the Sestrins, a family of poorly understood growth regulators (Sestrin1-Sestrin3), interact with GATOR2 in an amino-acid-sensitive fashion. Sestrin2-mediated inhibition of mTORC1 signaling requires GATOR1 and the Rag GTPases, and the Sestrins regulate the localization of mTORC1 in response to amino acids. Thus, we identify the Sestrins as GATOR2-interacting proteins that regulate the amino-acid-sensing branch of the mTORC1 pathway.
authors.affiliation: Department of Biology, Whitehead Institute for Biomedical Research and Massachusetts Institute of Technology, 9 Cambridge Center, Cambridge, MA 02142, USA; Department of Biology, Howard Hughes Medical Institute, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Koch Institute for Integrative Cancer Research, 77 Massachusetts Avenue, Cambridge, MA 02139, USA; Broad Institute of Harvard and Massachusetts Institute of Technology, 7 Cambridge Center, Cambridge MA 02142, USA.
authors.forename: Lynne
authors.initials: L
authors.lastname: Chantranupong
authors.affiliation: Department of Biology, Whitehead Institute for Biomedical Research and Massachusetts Institute of Technology, 9 Cambridge Center, Cambridge, MA 02142, USA; Department of Biology, Howard Hughes Medical Institute, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Koch Institute for Integrative Cancer Research, 77 Massachusetts Avenue, Cambridge, MA 02139, USA; Broad Institute of Harvard and Massachusetts Institute of Technology, 7 Cambridge Center, Cambridge MA 02142, USA.
authors.forename: Rachel L
authors.initials: RL
authors.lastname: Wolfson
authors.affiliation: Department of Biology, Whitehead Institute for Biomedical Research and Massachusetts Institute of Technology, 9 Cambridge Center, Cambridge, MA 02142, USA; Department of Biology, Howard Hughes Medical Institute, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Koch Institute for Integrative Cancer Research, 77 Massachusetts Avenue, Cambridge, MA 02139, USA; Broad Institute of Harvard and Massachusetts Institute of Technology, 7 Cambridge Center, Cambridge MA 02142, USA.
authors.forename: Jose M
authors.initials: JM
authors.lastname: Orozco
authors.affiliation: Department of Biology, Whitehead Institute for Biomedical Research and Massachusetts Institute of Technology, 9 Cambridge Center, Cambridge, MA 02142, USA; Department of Biology, Howard Hughes Medical Institute, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Koch Institute for Integrative Cancer Research, 77 Massachusetts Avenue, Cambridge, MA 02139, USA; Broad Institute of Harvard and Massachusetts Institute of Technology, 7 Cambridge Center, Cambridge MA 02142, USA.
authors.forename: Robert A
authors.initials: RA
authors.lastname: Saxton
authors.affiliation: Department of Biology, Whitehead Institute for Biomedical Research and Massachusetts Institute of Technology, 9 Cambridge Center, Cambridge, MA 02142, USA; Department of Biology, Howard Hughes Medical Institute, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
authors.forename: Sonia M
authors.initials: SM
authors.lastname: Scaria
authors.affiliation: Department of Biology, Whitehead Institute for Biomedical Research and Massachusetts Institute of Technology, 9 Cambridge Center, Cambridge, MA 02142, USA; Department of Biology, Howard Hughes Medical Institute, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Koch Institute for Integrative Cancer Research, 77 Massachusetts Avenue, Cambridge, MA 02139, USA; Broad Institute of Harvard and Massachusetts Institute of Technology, 7 Cambridge Center, Cambridge MA 02142, USA.
authors.forename: Liron
authors.initials: L
authors.lastname: Bar-Peled
authors.affiliation: Department of Biology, Whitehead Institute for Biomedical Research and Massachusetts Institute of Technology, 9 Cambridge Center, Cambridge, MA 02142, USA.
authors.forename: Eric
authors.initials: E
authors.lastname: Spooner
authors.affiliation: Department of Cell Biology, Harvard Medical School, 240 Longwood Avenue, Boston, MA 02115, USA.
authors.forename: Marta
authors.initials: M
authors.lastname: Isasa
authors.affiliation: Department of Cell Biology, Harvard Medical School, 240 Longwood Avenue, Boston, MA 02115, USA.
authors.forename: Steven P
authors.initials: SP
authors.lastname: Gygi
authors.affiliation: Department of Biology, Whitehead Institute for Biomedical Research and Massachusetts Institute of Technology, 9 Cambridge Center, Cambridge, MA 02142, USA; Department of Biology, Howard Hughes Medical Institute, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Koch Institute for Integrative Cancer Research, 77 Massachusetts Avenue, Cambridge, MA 02139, USA; Broad Institute of Harvard and Massachusetts Institute of Technology, 7 Cambridge Center, Cambridge MA 02142, USA. Electronic address: sabatini@wi.mit.edu.
authors.forename: David M
authors.initials: DM
authors.lastname: Sabatini
mesh_terms: D000596:Amino Acids / Q000378:metabolism*; D057809:HEK293 Cells; D006360:Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D000076222:Mechanistic Target of Rapamycin Complex 1; D046912:Multiprotein Complexes / Q000235:genetics / Q000378:metabolism*; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D000084622:Sestrins
chemical_list: D000596:Amino Acids; D006360:Heat-Shock Proteins; D000076222:Mechanistic Target of Rapamycin Complex 1; D046912:Multiprotein Complexes; D009687:Nuclear Proteins; D058570:TOR Serine-Threonine Kinases; C117338:SESN1 protein, human; D000084622:Sestrins; C465398:SESN2 protein, human; C485523:SESN3 protein, human