Sestrins inhibit mTORC1 kinase activation through the GATOR complex

Cell Rep. 2014 Nov 20;9(4):1281-91. doi: 10.1016/j.celrep.2014.10.019.

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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • AMP-Activated Protein Kinases / metabolism
  • Amino Acids / metabolism
  • Animals
  • Enzyme Activation / drug effects
  • GTP Phosphohydrolases / metabolism
  • HEK293 Cells
  • Humans
  • Lysosomes / drug effects
  • Lysosomes / metabolism
  • Mechanistic Target of Rapamycin Complex 1
  • Mice
  • Multiprotein Complexes / metabolism*
  • Nuclear Proteins / metabolism*
  • Peroxidases
  • Phosphorylation / drug effects
  • Protein Binding / drug effects
  • Protein Transport / drug effects
  • Ribosomal Protein S6 Kinases, 70-kDa / metabolism
  • Rotenone / pharmacology
  • Signal Transduction / drug effects
  • TOR Serine-Threonine Kinases / metabolism*
  • Tunicamycin / pharmacology

Substances

  • Amino Acids
  • Multiprotein Complexes
  • Nuclear Proteins
  • SESN2 protein, human
  • Rotenone
  • Tunicamycin
  • Peroxidases
  • sestrin 2 protein, mouse
  • TOR Serine-Threonine Kinases
  • Mechanistic Target of Rapamycin Complex 1
  • Ribosomal Protein S6 Kinases, 70-kDa
  • AMP-Activated Protein Kinases
  • GTP Phosphohydrolases