Abstract
A protein synthesis enzyme, leucyl-tRNA synthetase (LRS), serves as a leucine sensor for the mechanistic target of rapamycin complex 1 (mTORC1), which is a central effector for protein synthesis, metabolism, autophagy, and cell growth. However, its significance in mTORC1 signaling and cancer growth and its functional relationship with other suggested leucine signal mediators are not well-understood. Here we show the kinetics of the Rag GTPase cycle during leucine signaling and that LRS serves as an initiating “ON” switch via GTP hydrolysis of RagD that drives the entire Rag GTPase cycle, whereas Sestrin2 functions as an “OFF” switch by controlling GTP hydrolysis of RagB in the Rag GTPase–mTORC1 axis. The LRS–RagD axis showed a positive correlation with mTORC1 activity in cancer tissues and cells. The GTP–GDP cycle of the RagD–RagB pair, rather than the RagC–RagA pair, is critical for leucine-induced mTORC1 activation. The active RagD–RagB pair can overcome the absence of the RagC–RagA pair, but the opposite is not the case. This work suggests that the GTPase cycle of RagD–RagB coordinated by LRS and Sestrin2 is critical for controlling mTORC1 activation, and thus will extend the current understanding of the amino acid-sensing mechanism.
Original language | English |
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Pages (from-to) | E5279-E5288 |
Journal | Proceedings of the National Academy of Sciences of the United States of America |
Volume | 115 |
Issue number | 23 |
DOIs | |
Publication status | Published - 2018 Jun 5 |
Bibliographical note
Funding Information:This work was supported by Global Frontier Project Grants NRF-2013M3A6A4072536 and NRF-M3A6A4-2010-0029785 and by a grant from the Gyeonggi Research Development Program.
Funding Information:
ACKNOWLEDGMENTS. This work was supported by Global Frontier Project Grants NRF-2013M3A6A4072536 and NRF-M3A6A4-2010-0029785 and by a grant from the Gyeonggi Research Development Program.
Publisher Copyright:
© 2018 National Academy of Sciences. All Rights Reserved.
All Science Journal Classification (ASJC) codes
- General