title: Sestrins inhibit mTORC1 kinase activation through the GATOR complex.
abstract: The mechanistic target of rapamycin complex 1 (mTORC1) kinase is a sensor of different environmental conditions and regulator of cell growth, metabolism, and autophagy. mTORC1 is activated by Rag GTPases, working as RagA:RagB and RagC:RagD heterodimers. Rags control mTORC1 activity by tethering mTORC1 to the lysosomes where it is activated by Rheb GTPase. RagA:RagB, active in its GTP-bound form, is inhibited by GATOR1 complex, a GTPase-activating protein, and GATOR1 is in turn negatively regulated by GATOR2 complex. Sestrins are stress-responsive proteins that inhibit mTORC1 via activation of AMP-activated protein kinase (AMPK) and tuberous sclerosis complex. Here we report an AMPK-independent mechanism of mTORC1 inhibition by Sestrins mediated by their interaction with GATOR2. As a result of this interaction, the Sestrins suppress mTOR lysosomal localization in a Rag-dependent manner. This mechanism is potentially involved in mTORC1 regulation by amino acids, rotenone, and tunicamycin, connecting stress response with mTORC1 inhibition.
authors.forename: Anita
authors.initials: A
authors.lastname: Parmigiani
authors.forename: Aida
authors.initials: A
authors.lastname: Nourbakhsh
authors.forename: Boxiao
authors.initials: B
authors.lastname: Ding
authors.forename: Wei
authors.initials: W
authors.lastname: Wang
authors.forename: Young Chul
authors.initials: YC
authors.lastname: Kim
authors.forename: Konstantin
authors.initials: K
authors.lastname: Akopiants
authors.forename: Kun-Liang
authors.initials: KL
authors.lastname: Guan
authors.forename: Michael
authors.initials: M
authors.lastname: Karin
authors.forename: Andrei V
authors.initials: AV
authors.lastname: Budanov
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism; D000596:Amino Acids / Q000378:metabolism; D000818:Animals; D004789:Enzyme Activation / Q000187:drug effects; D020558:GTP Phosphohydrolases / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D008247:Lysosomes / Q000187:drug effects / Q000378:metabolism; D000076222:Mechanistic Target of Rapamycin Complex 1; D051379:Mice; D046912:Multiprotein Complexes / Q000378:metabolism*; D009687:Nuclear Proteins / Q000378:metabolism*; D010544:Peroxidases; D010766:Phosphorylation / Q000187:drug effects; D011485:Protein Binding / Q000187:drug effects; D021381:Protein Transport / Q000187:drug effects; D038762:Ribosomal Protein S6 Kinases, 70-kDa / Q000378:metabolism; D012402:Rotenone / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*; D014415:Tunicamycin / Q000494:pharmacology; D000084622:Sestrins
chemical_list: D055372:AMP-Activated Protein Kinases; D000596:Amino Acids; D020558:GTP Phosphohydrolases; D000076222:Mechanistic Target of Rapamycin Complex 1; D046912:Multiprotein Complexes; D009687:Nuclear Proteins; D010544:Peroxidases; D038762:Ribosomal Protein S6 Kinases, 70-kDa; D012402:Rotenone; D058570:TOR Serine-Threonine Kinases; D014415:Tunicamycin; C465398:SESN2 protein, human; D000084622:Sestrins; C529380:Sesn2 protein, mouse