title: GCN2 sustains mTORC1 suppression upon amino acid deprivation by inducing Sestrin2.
abstract: Mammalian cells possess two amino acid-sensing kinases: general control nonderepressible 2 (GCN2) and mechanistic target of rapamycin complex 1 (mTORC1). Their combined effects orchestrate cellular adaptation to amino acid levels, but how their activities are coordinated remains poorly understood. Here, we demonstrate an important link between GCN2 and mTORC1 signaling. Upon deprivation of various amino acids, activated GCN2 up-regulates ATF4 to induce expression of the stress response protein Sestrin2, which is required to sustain repression of mTORC1 by blocking its lysosomal localization. Moreover, Sestrin2 induction is necessary for cell survival during glutamine deprivation, indicating that Sestrin2 is a critical effector of GCN2 signaling that regulates amino acid homeostasis through mTORC1 suppression.
authors.affiliation: Cancer Biology and Genetics Program, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA;
authors.forename: Jiangbin
authors.initials: J
authors.lastname: Ye
authors.affiliation: Cancer Biology and Genetics Program, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA;
authors.forename: Wilhelm
authors.initials: W
authors.lastname: Palm
authors.affiliation: Immunology Program, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA;
authors.forename: Min
authors.initials: M
authors.lastname: Peng
authors.affiliation: Cancer Biology and Genetics Program, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA;
authors.forename: Bryan
authors.initials: B
authors.lastname: King
authors.affiliation: Immunology Program, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA;
authors.forename: Tullia
authors.initials: T
authors.lastname: Lindsten
authors.affiliation: Immunology Program, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA;
authors.forename: Ming O
authors.initials: MO
authors.lastname: Li
authors.affiliation: Department of Radiation Oncology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
authors.forename: Constantinos
authors.initials: C
authors.lastname: Koumenis
authors.affiliation: Cancer Biology and Genetics Program, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA;
authors.forename: Craig B
authors.initials: CB
authors.lastname: Thompson
mesh_terms: D051701:Activating Transcription Factor 4 / Q000235:genetics / Q000378:metabolism; D000596:Amino Acids / Q000378:metabolism*; D000818:Animals; D002460:Cell Line; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000235:genetics; D005786:Gene Expression Regulation; D057809:HEK293 Cells; D006801:Humans; D008247:Lysosomes / Q000378:metabolism; D000076222:Mechanistic Target of Rapamycin Complex 1; D051379:Mice; D046912:Multiprotein Complexes / Q000378:metabolism*; D009687:Nuclear Proteins / Q000235:genetics* / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*; D000084622:Sestrins
chemical_list: D051701:Activating Transcription Factor 4; D000596:Amino Acids; D000076222:Mechanistic Target of Rapamycin Complex 1; D046912:Multiprotein Complexes; D009687:Nuclear Proteins; D017346:Protein Serine-Threonine Kinases; D058570:TOR Serine-Threonine Kinases; C497109:ATF4 protein, human; C465398:SESN2 protein, human; D000084622:Sestrins; C529271:EIF2AK4 protein, human
keywords: GCN2; Sestrin; amino acid deprivation; mTORC1