Sestrins Inhibit mTORC1 Kinase Activation through the GATOR Complex

Autor: Anita Parmigiani, Aida Nourbakhsh, Boxiao Ding, Wei Wang, Young Chul Kim, Konstantin Akopiants, Kun-Liang Guan, Michael Karin, Andrei V. Budanov
Jazyk: angličtina
Rok vydání: 2014
Předmět:
Zdroj: Cell Reports, Vol 9, Iss 4, Pp 1281-1291 (2014)
Druh dokumentu: article
ISSN: 2211-1247
DOI: 10.1016/j.celrep.2014.10.019
Popis: 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.
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