Sestrins inhibit mTORC1 kinase activation through the GATOR complex.
Item Type:Journal Article
Citation:Parmigiani, A., Nourbakhsh, A., Ding, B., Wang, W., Kim, Y.C., Akopiants, K., Guan, K.L., Karin, M. & Budanov, A.V., Sestrins inhibit mTORC1 kinase activation through the GATOR complex., Cell Reports, 9, 4, 2014, 1281 - 1291
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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.
Author: Budanov, Andrei; Parmigiani, Anita; Nourbakhsh, Aida; Ding, Boxiao; Wang, Wei; Kim, Young Chul; Akopiants, Konstantin; Guan, Kun-Liang; Karin, Michael
Type of material:Journal Article
Series/Report no:Cell Reports;
Availability:Full text available