Sestrins Inhibit mTORC1 Kinase Activation through the GATOR Complex

• Sestrins interact with GATOR2 via WDR24 and Seh1L in a stress-regulated manner
• Sesn2 inhibits mTORC1 activity via GATOR regulation
• Sesn2 inhibits mTOR lysosomal localization via a Rag-dependent mechanism
• Sesn2 mediates inhibition of mTORC1 by stress in an AMPK-independent manner

SummaryThe 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.

Graphical AbstractFigure optionsDownload as PowerPoint slide