title: Redox regulates mammalian target of rapamycin complex 1 (mTORC1) activity by modulating the TSC1/TSC2-Rheb GTPase pathway.
abstract: Mammalian target of rapamycin (mTOR) is a kinase that plays a key role in a wide array of cellular processes and exists in two distinct functional complexes, mTOR complex 1 (mTORC1) and mTOR complex 2 (mTORC2). Although mTORC2 is primarily activated by growth factors, mTORC1 is regulated by numerous extracellular and intracellular signals such as nutrients, growth factors, and cellular redox. Previous study has shown that cysteine oxidants sufficiently activate mTORC1 activity under amino acid-depleted conditions and that a reducing agent effectively suppresses amino acid-induced mTORC1 activity, thereby raising the possibility that redox-sensitive mechanisms underlie amino acid-dependent mTORC1 regulation. However, the molecular mechanism by which redox regulates mTORC1 activity is not well understood. In this study, we show that the redox-sensitive regulation of mTORC1 occurs via Rheb but not the Rag small GTPase. Enhancing cellular redox potential with cysteine oxidants significantly increases Rheb GTP levels. Importantly, modulation of the cellular redox potential with a cysteine oxidant or reducing agent failed to alter mTORC1 activity in TSC1(-/-) or TSC2(-/-) mouse embryonic fibroblast cells. Furthermore, a cysteine oxidant has little effect on mTOR localization but sufficiently activates mTORC1 activity in both p18(-/-) and control mouse embryonic fibroblast cells, suggesting that the redox-sensitive regulation of mTORC1 occurs independent of the Ragulator·Rag complex. Taken together, our results suggest that the TSC complex plays an important role in redox-sensitive mTORC1 regulation and argues for the activation of mTORC1 in places other than the lysosome upon inhibition of the TSC complex.
authors.affiliation: Life Sciences Institute, University of Michigan, Ann Arbor, Michigan 48109, USA.
authors.forename: Sei
authors.initials: S
authors.lastname: Yoshida
authors.forename: Sungki
authors.initials: S
authors.lastname: Hong
authors.forename: Tsukasa
authors.initials: T
authors.lastname: Suzuki
authors.forename: Shigeyuki
authors.initials: S
authors.lastname: Nada
authors.forename: Aristotle M
authors.initials: AM
authors.lastname: Mannan
authors.forename: Junying
authors.initials: J
authors.lastname: Wang
authors.forename: Masato
authors.initials: M
authors.lastname: Okada
authors.forename: Kun-Liang
authors.initials: KL
authors.lastname: Guan
authors.forename: Ken
authors.initials: K
authors.lastname: Inoki
mesh_terms: D000818:Animals; D004622:Embryo, Mammalian / Q000166:cytology / Q000378:metabolism; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism; D057809:HEK293 Cells; D006367:HeLa Cells; D006801:Humans; D008247:Lysosomes / Q000235:genetics / Q000378:metabolism; D000076222:Mechanistic Target of Rapamycin Complex 1; D051379:Mice; D018345:Mice, Knockout; D020559:Monomeric GTP-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D046912:Multiprotein Complexes; D009479:Neuropeptides / Q000235:genetics / Q000378:metabolism*; D010084:Oxidation-Reduction; D021381:Protein Transport / Q000502:physiology; D011506:Proteins / Q000235:genetics / Q000378:metabolism*; D000076205:Ras Homolog Enriched in Brain Protein; D058570:TOR Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D000077004:Tuberous Sclerosis Complex 1 Protein; D000077005:Tuberous Sclerosis Complex 2 Protein; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D046912:Multiprotein Complexes; D009479:Neuropeptides; D011506:Proteins; C490211:RHEB protein, human; D000076205:Ras Homolog Enriched in Brain Protein; C490213:Rheb protein, mouse; C000624650:TSC1 protein, human; C000624653:TSC2 protein, human; C000624651:Tsc1 protein, mouse; C000624654:Tsc2 protein, mouse; D000077004:Tuberous Sclerosis Complex 1 Protein; D000077005:Tuberous Sclerosis Complex 2 Protein; D025521:Tumor Suppressor Proteins; C546842:MTOR protein, human; C546843:mTOR protein, mouse; D000076222:Mechanistic Target of Rapamycin Complex 1; D058570:TOR Serine-Threonine Kinases; D020559:Monomeric GTP-Binding Proteins