title: Sestrin2 inhibits mTORC1 through modulation of GATOR complexes.
abstract: Sestrins are stress-inducible metabolic regulators that suppress a wide range of age- and obesity-associated pathologies, many of which are due to mTORC1 overactivation. Upon various stresses, the Sestrins inhibit mTORC1 activity through an indirect mechanism that is still unclear. GATORs are recently identified protein complexes that regulate the activity of RagB, a small GTPase essential for mTORC1 activation. GATOR1 is a GTPase activating protein (GAP) for RagB whereas GATOR2 functions as an inhibitor of GATOR1. However, how the GATORs are physiologically regulated is unknown. Here we show that Sestrin2 binds to GATOR2, and liberates GATOR1 from GATOR2-mediated inhibition. Released GATOR1 subsequently binds to and inactivates RagB, ultimately resulting in mTORC1 suppression. Consistent with this biochemical mechanism, genetic ablation of GATOR1 nullifies the mTORC1-inhibiting effect of Sestrin2 in both cell culture and Drosophila models. Collectively, we elucidate a new signaling cascade composed of Sestrin2-GATOR2-GATOR1-RagB that mediates stress-dependent suppression of mTORC1 activity.
authors.affiliation: 1] Department of Molecular &Integrative Physiology, University of Michigan, Ann Arbor, MI 48109, USA [2] Department of Obstetrics and Gynecology, Soonchunhyang University Seoul Hospital, Seoul 140-743, Republic of Korea.
authors.forename: Jeong Sig
authors.initials: JS
authors.lastname: Kim
authors.affiliation: Department of Molecular &Integrative Physiology, University of Michigan, Ann Arbor, MI 48109, USA.
authors.forename: Seung-Hyun
authors.initials: SH
authors.lastname: Ro
authors.affiliation: Department of Molecular &Integrative Physiology, University of Michigan, Ann Arbor, MI 48109, USA.
authors.forename: Myungjin
authors.initials: M
authors.lastname: Kim
authors.affiliation: Department of Molecular &Integrative Physiology, University of Michigan, Ann Arbor, MI 48109, USA.
authors.forename: Hwan-Woo
authors.initials: HW
authors.lastname: Park
authors.affiliation: Department of Molecular &Integrative Physiology, University of Michigan, Ann Arbor, MI 48109, USA.
authors.forename: Ian A
authors.initials: IA
authors.lastname: Semple
authors.affiliation: Department of Molecular &Integrative Physiology, University of Michigan, Ann Arbor, MI 48109, USA.
authors.forename: Haeli
authors.initials: H
authors.lastname: Park
authors.affiliation: Department of Biological Chemistry, University of Michigan, Ann Arbor, MI 48109, USA.
authors.forename: Uhn-Soo
authors.initials: US
authors.lastname: Cho
authors.affiliation: Department of Pharmacology, University of California, San Diego, CA 92093, USA.
authors.forename: Wei
authors.initials: W
authors.lastname: Wang
authors.affiliation: Department of Pharmacology, University of California, San Diego, CA 92093, USA.
authors.forename: Kun-Liang
authors.initials: KL
authors.lastname: Guan
authors.affiliation: Department of Pharmacology, University of California, San Diego, CA 92093, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Karin
authors.affiliation: Department of Molecular &Integrative Physiology, University of Michigan, Ann Arbor, MI 48109, USA.
authors.forename: Jun Hee
authors.initials: JH
authors.lastname: Lee
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism; D000818:Animals; D001343:Autophagy; D004330:Drosophila / Q000378:metabolism; D005347:Fibroblasts / Q000378:metabolism; D020690:GTPase-Activating Proteins / Q000378:metabolism*; D057809:HEK293 Cells; D006801:Humans; D007425:Intracellular Membranes / Q000378:metabolism; D042541:Intracellular Space / Q000378:metabolism; D008247:Lysosomes / Q000378:metabolism; D000076222:Mechanistic Target of Rapamycin Complex 1; D051379:Mice; D020559:Monomeric GTP-Binding Proteins / Q000378:metabolism; D046912:Multiprotein Complexes / Q000037:antagonists & inhibitors / Q000378:metabolism*; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D011485:Protein Binding; D021381:Protein Transport; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000084622:Sestrins
chemical_list: D055372:AMP-Activated Protein Kinases; D020690:GTPase-Activating Proteins; D000076222:Mechanistic Target of Rapamycin Complex 1; D020559:Monomeric GTP-Binding Proteins; D046912:Multiprotein Complexes; D009687:Nuclear Proteins; D058570:TOR Serine-Threonine Kinases; C465398:SESN2 protein, human; D000084622:Sestrins
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