Leucyl-tRNA Synthetase Activates Vps34 in Amino Acid-Sensing mTORC1 Signaling

Mee Sup Yoon; Kook Son; Edwin Arauz; Jung Min Han; Sunghoon Kim; Jie Chen

doi:10.1016/j.celrep.2016.07.008

Leucyl-tRNA Synthetase Activates Vps34 in Amino Acid-Sensing mTORC1 Signaling

Mee Sup Yoon, Kook Son, Edwin Arauz, Jung Min Han, Sunghoon Kim, Jie Chen

Research output: Contribution to journal › Article › peer-review

66 Citations (Scopus)

Abstract

Amino acid availability activates signaling by the mammalian target of rapamycin (mTOR) complex 1, mTORC1, a master regulator of cell growth. The class III PI-3-kinase Vps34 mediates amino acid signaling to mTORC1 by regulating lysosomal translocation and activation of the phospholipase PLD1. Here, we identify leucyl-tRNA synthetase (LRS) as a leucine sensor for the activation of Vps34-PLD1 upstream of mTORC1. LRS is necessary for amino acid-induced Vps34 activation, cellular PI(3)P level increase, PLD1 activation, and PLD1 lysosomal translocation. Leucine binding, but not tRNA charging activity of LRS, is required for this regulation. Moreover, LRS physically interacts with Vps34 in amino acid-stimulatable non-autophagic complexes. Finally, purified LRS protein activates Vps34 kinase in vitro in a leucine-dependent manner. Collectively, our findings provide compelling evidence for a direct role of LRS in amino acid activation of Vps34 via a non-canonical mechanism and fill a gap in the amino acid-sensing mTORC1 signaling network.

Original language	English
Pages (from-to)	1510-1517
Number of pages	8
Journal	Cell Reports
Volume	16
Issue number	6
DOIs	https://doi.org/10.1016/j.celrep.2016.07.008
Publication status	Published - 2016 Aug 9

Bibliographical note

Funding Information:
This paper is dedicated to the occasion of Professor Stuart L. Schreiber’s 60 th birthday. We are most grateful to Professor Schreiber for his scientific vision and mentoring. We also thank Christina L. Rosenberger for critical reading and editing of the manuscript. This work was supported by grants from the NIH (R01 AR048914 and GM089771 to J.C.), the Keck Foundation (to J.C.), the Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education (2015R1D1A1A01058313 to M.-S.Y.), and the Gachon University Gil Medical Center (2015-15 to M.-S.Y.).

Publisher Copyright:
© 2016 The Author(s)

All Science Journal Classification (ASJC) codes

Biochemistry, Genetics and Molecular Biology(all)

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10.1016/j.celrep.2016.07.008

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title = "Leucyl-tRNA Synthetase Activates Vps34 in Amino Acid-Sensing mTORC1 Signaling",

abstract = "Amino acid availability activates signaling by the mammalian target of rapamycin (mTOR) complex 1, mTORC1, a master regulator of cell growth. The class III PI-3-kinase Vps34 mediates amino acid signaling to mTORC1 by regulating lysosomal translocation and activation of the phospholipase PLD1. Here, we identify leucyl-tRNA synthetase (LRS) as a leucine sensor for the activation of Vps34-PLD1 upstream of mTORC1. LRS is necessary for amino acid-induced Vps34 activation, cellular PI(3)P level increase, PLD1 activation, and PLD1 lysosomal translocation. Leucine binding, but not tRNA charging activity of LRS, is required for this regulation. Moreover, LRS physically interacts with Vps34 in amino acid-stimulatable non-autophagic complexes. Finally, purified LRS protein activates Vps34 kinase in vitro in a leucine-dependent manner. Collectively, our findings provide compelling evidence for a direct role of LRS in amino acid activation of Vps34 via a non-canonical mechanism and fill a gap in the amino acid-sensing mTORC1 signaling network.",

author = "Yoon, {Mee Sup} and Kook Son and Edwin Arauz and Han, {Jung Min} and Sunghoon Kim and Jie Chen",

note = "Funding Information: This paper is dedicated to the occasion of Professor Stuart L. Schreiber{\textquoteright}s 60 th birthday. We are most grateful to Professor Schreiber for his scientific vision and mentoring. We also thank Christina L. Rosenberger for critical reading and editing of the manuscript. This work was supported by grants from the NIH (R01 AR048914 and GM089771 to J.C.), the Keck Foundation (to J.C.), the Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education (2015R1D1A1A01058313 to M.-S.Y.), and the Gachon University Gil Medical Center (2015-15 to M.-S.Y.). Publisher Copyright: {\textcopyright} 2016 The Author(s)",

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AU - Kim, Sunghoon

AU - Chen, Jie

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Leucyl-tRNA Synthetase Activates Vps34 in Amino Acid-Sensing mTORC1 Signaling

Abstract

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