Mitochondrial Threonyl-tRNA Synthetase TARS2 Is Required for Threonine-Sensitive mTORC1 Activation

Mol Cell. 2021 Jan 21;81(2):398-407.e4. doi: 10.1016/j.molcel.2020.11.036. Epub 2020 Dec 18.

Abstract

Mechanistic target of rapamycin complex 1 (mTORC1) controls cell growth and proliferation by sensing fluctuations in environmental cues such as nutrients, growth factors, and energy levels. The Rag GTPases (Rags) serve as a critical module that signals amino acid (AA) availability to modulate mTORC1 localization and activity. Recent studies have demonstrated how AAs regulate mTORC1 activity through Rags. Here, we uncover an unconventional pathway that activates mTORC1 in response to variations in threonine (Thr) levels via mitochondrial threonyl-tRNA synthetase TARS2. TARS2 interacts with inactive Rags, particularly GTP-RagC, leading to increased GTP loading of RagA. mTORC1 activity in cells lacking TARS2 is resistant to Thr repletion, showing that TARS2 is necessary for Thr-dependent mTORC1 activation. The requirement of TARS2, but not cytoplasmic threonyl-tRNA synthetase TARS, for this effect demonstrates an additional layer of complexity in the regulation of mTORC1 activity.

Keywords: Rag GTPases; TARS2; amino acid; aminoacyl-tRNA synthetase; mTORC1; threonine.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Gene Expression Regulation
  • Guanosine Diphosphate / metabolism
  • Guanosine Triphosphate / metabolism
  • HEK293 Cells
  • Humans
  • Isoenzymes / antagonists & inhibitors
  • Isoenzymes / genetics
  • Isoenzymes / metabolism
  • Lysosomes / metabolism
  • Mechanistic Target of Rapamycin Complex 1 / genetics*
  • Mechanistic Target of Rapamycin Complex 1 / metabolism
  • Mitochondria / metabolism*
  • Monomeric GTP-Binding Proteins / genetics*
  • Monomeric GTP-Binding Proteins / metabolism
  • Protein Binding
  • RNA, Small Interfering / genetics
  • RNA, Small Interfering / metabolism
  • Regulatory-Associated Protein of mTOR / genetics
  • Regulatory-Associated Protein of mTOR / metabolism
  • Signal Transduction
  • Threonine / metabolism*
  • Threonine-tRNA Ligase / antagonists & inhibitors
  • Threonine-tRNA Ligase / genetics*
  • Threonine-tRNA Ligase / metabolism

Substances

  • Isoenzymes
  • RNA, Small Interfering
  • RPTOR protein, human
  • RRAGC protein, human
  • Regulatory-Associated Protein of mTOR
  • Guanosine Diphosphate
  • Threonine
  • Guanosine Triphosphate
  • Mechanistic Target of Rapamycin Complex 1
  • RRAGA protein, human
  • Monomeric GTP-Binding Proteins
  • Threonine-tRNA Ligase