한빛사 논문
Sung-Hoon Kim1,2, Jung-Hyun Choi1,2, Peng Wang1,2, Christopher D. Go3,4, Geoffrey G. Hesketh3, Anne-Claude Gingras3,4, Seyed Mehdi Jafarnejad5,*, Nahum Sonenberg1,2,6,*
1Goodman Cancer Research Centre, McGill University, Montreal, QC H3A 1A3, Canada
2Department of Biochemistry, McGill University, Montreal, QC H3A 1A3, Canada
3Centre for Systems Biology, Lunenfeld-Tanenbaum Research Institute, Sinai Health System, Toronto, ON M5G 1X5, Canada
4Department of Molecular Genetics, University of Toronto, Toronto, ON M5S 1A1, Canada
5Patrick G. Johnston Centre for Cancer Research, Queen’s University Belfast, Belfast BT9 7AE, UK
*Corresponding author
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.
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