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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.

SUBMITTER: Parmigiani A

PROVIDER: S-EPMC4303546 | biostudies-literature | 2014 Nov

REPOSITORIES: biostudies-literature

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Sestrins inhibit mTORC1 kinase activation through the GATOR complex.

Parmigiani Anita A Nourbakhsh Aida A Ding Boxiao B Wang Wei W Kim Young Chul YC Akopiants Konstantin K Guan Kun-Liang KL Karin Michael M Budanov Andrei V AV

Cell reports 20141101 4

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 regulat ...[more]

PMID: 25457612

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Project description:BackgroundSestrins (SESN1-3) act as proximal sensors in leucine-induced activation of the protein kinase mechanistic target of rapamycin (mTOR) in complex 1 (mTORC1), a key regulator of cell growth and metabolism.ObjectiveIn the present study, the hypothesis that SESNs also mediate glucose-induced activation of mTORC1 was tested.MethodsRats underwent overnight fasting, and in the morning, either saline or a glucose solution (4 g⋅kg-1 BW/10 mL⋅kg-1) was administered by oral gavage; mTORC1 activation in the tibialis anterior muscle was assessed. To further assess the mechanism through which glucose promotes mTORC1 activation, wild-type (WT) HEK293T and HEK293T cells lacking either all 3 SESNs (SESNTKO) or hexokinase 2 (HK2KO) were deprived of glucose, followed by glucose addback, and mTORC1 activation was assessed. In addition, glucose-induced changes in the association of the SESNs with components of the GAP activity toward the Rags (GATOR2) complex and with hexokinase 2 (HK2) were assessed by co-immunoprecipitation. One- and two-way ANOVA with Tukey post hoc comparisons were used.ResultsGlucose administration to fasted rats promoted mTORC1 activation. Similarly, glucose readdition (GluAB) to the medium of glucose-deprived WT cells also promoted mTORC1 activation. By contrast, SESNTKO cells demonstrated attenuated mTORC1 activation following GluAB compared with WT cells. Interestingly, HK2 associated with all 3 SESNs in a glucose-dependent manner, i.e., HK2 abundance in SESN immunoprecipitates was high in cells deprived of glucose and decreased in response to GluAB. Moreover, similar to SESNTKO cells, the sensitivity of mTORC1 to GluAB was attenuated in HK2KO cells compared with WT cells.ConclusionsThe results of this study demonstrate that the SESNs and HK2 play important roles in glucose-induced mTORC1 activation in HEK293T cells. However, unlike leucine-induced mTORC1 activation, the effect was independent of the changes in SESN-GATOR2 interaction, and instead, it was associated with alterations in the association of SESNs with HK2.

Dataset Information

Sestrins inhibit mTORC1 kinase activation through the GATOR complex.

Publications

Sestrins inhibit mTORC1 kinase activation through the GATOR complex.

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