GCN2 contributes to mTORC1 inhibition by leucine deprivation through an ATF4 independent mechanism.

Julien Averous,Florent Mesclon,Philippe Pierre,Laurent Parry,Alain Bruhat,Sarah Lambert-Langlais,Céline Jousse,Pierre Fafournoux,Christopher G Proud,Valérie Carraro,Anne-Catherine Maurin

doi:10.1038/srep27698

Abstract

It is well known that the GCN2 and mTORC1 signaling pathways are regulated by amino acids and share common functions, in particular the control of translation. The regulation of GCN2 activity by amino acid availability relies on the capacity of GCN2 to sense the increased levels of uncharged tRNAs upon amino acid scarcity. In contrast, despite recent progress in the understanding of the regulation of mTORC1 by amino acids, key aspects of this process remain unsolved. In particular, while leucine is well known to be a potent regulator of mTORC1, the mechanisms by which this amino acid is sensed and control mTORC1 activity are not well defined. Our data establish that GCN2 is involved in the inhibition of mTORC1 upon leucine or arginine deprivation. However, the activation of GCN2 alone is not sufficient to inhibit mTORC1 activity, indicating that leucine and arginine exert regulation via additional mechanisms. While the mechanism by which GCN2 contributes to the initial step of mTORC1 inhibition involves the phosphorylation of eIF2α, we show that it is independent of the downstream transcription factor ATF4. These data point to a novel role for GCN2 and phosphorylation of eIF2α in the control of mTORC1 by certain amino acids.

Highlights

To cite this version: Julien Averous, Sarah Lambert-Langlais, Florent Mesclon, Valerie Carraro, Laurent Parry, et al
While the mechanism by which GCN2 contributes to the initial step of mTORC1 inhibition involves the phosphorylation of eIF2α, we show that it is independent of the downstream transcription factor activating transcription factor 4 (ATF4)
To examine the role of GCN2 in the inhibition of mTORC1 activity we first performed a time-course of leucine deprivation in mouse embryonic fibroblasts (MEFs)

Summary

Introduction

To cite this version: Julien Averous, Sarah Lambert-Langlais, Florent Mesclon, Valerie Carraro, Laurent Parry, et al. While the mechanism by which GCN2 contributes to the initial step of mTORC1 inhibition involves the phosphorylation of eIF2α, we show that it is independent of the downstream transcription factor ATF4. These data point to a novel role for GCN2 and phosphorylation of eIF2α in the control of mTORC1 by certain amino acids. GCN2 is activated during scarcity of an essential amino acid and phosphorylates the α-subunit of eukaryotic initiation factor 2 alpha (eIF2α)[4]. This leads to the general inhibition of protein synthesis. ATF4 plays a key role in the adaptation of the cell to the lack of amino acids by regulating the expression, of amino acid transporters[6], enzymes involved in amino acid metabolism[7] or factors involved in autophagy[8]

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Conclusion