GCN2 contributes to mTORC1 inhibition by leucine deprivation through an ATF4 independent mechanism.
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.
INRA, UMR 1019 Nutrition Humaine, Centre de Clermont-Ferrand-Theix, F-63122 Saint Genès Champanelle, France.|Université Clermont 1, UFR Médecine, UMR 1019 Nutrition Humaine, Clermont-Ferrand, France.
Julien
J
Averous
INRA, UMR 1019 Nutrition Humaine, Centre de Clermont-Ferrand-Theix, F-63122 Saint Genès Champanelle, France.|Université Clermont 1, UFR Médecine, UMR 1019 Nutrition Humaine, Clermont-Ferrand, France.
Sarah
S
Lambert-Langlais
INRA, UMR 1019 Nutrition Humaine, Centre de Clermont-Ferrand-Theix, F-63122 Saint Genès Champanelle, France.|Université Clermont 1, UFR Médecine, UMR 1019 Nutrition Humaine, Clermont-Ferrand, France.
Florent
F
Mesclon
INRA, UMR 1019 Nutrition Humaine, Centre de Clermont-Ferrand-Theix, F-63122 Saint Genès Champanelle, France.|Université Clermont 1, UFR Médecine, UMR 1019 Nutrition Humaine, Clermont-Ferrand, France.
Valérie
V
Carraro
INRA, UMR 1019 Nutrition Humaine, Centre de Clermont-Ferrand-Theix, F-63122 Saint Genès Champanelle, France.|Université Clermont 1, UFR Médecine, UMR 1019 Nutrition Humaine, Clermont-Ferrand, France.
Laurent
L
Parry
INRA, UMR 1019 Nutrition Humaine, Centre de Clermont-Ferrand-Theix, F-63122 Saint Genès Champanelle, France.|Université Clermont 1, UFR Médecine, UMR 1019 Nutrition Humaine, Clermont-Ferrand, France.
Céline
C
Jousse
INRA, UMR 1019 Nutrition Humaine, Centre de Clermont-Ferrand-Theix, F-63122 Saint Genès Champanelle, France.|Université Clermont 1, UFR Médecine, UMR 1019 Nutrition Humaine, Clermont-Ferrand, France.
Alain
A
Bruhat
INRA, UMR 1019 Nutrition Humaine, Centre de Clermont-Ferrand-Theix, F-63122 Saint Genès Champanelle, France.|Université Clermont 1, UFR Médecine, UMR 1019 Nutrition Humaine, Clermont-Ferrand, France.
Anne-Catherine
AC
Maurin
Centre d'Immunologie de Marseille-Luminy, Aix-Marseille Université, U2M, 13288 Marseille, France.|INSERM, U1104, 13288 Marseille, France.|CNRS, UMR 7280, 13288 Marseille, France.|Institute for Research in Biomedicine - iBiMED and Aveiro Health Sciences Program, University of Aveiro, 3810-193 Aveiro, Portugal.
Philippe
P
Pierre
Nutrition and Metabolism, South Australian Health &Medical Research Institute, PO Box 11060, Adelaide, SA5001, Australia.|School of Biological Sciences, University of Adelaide, Australia.
Christopher G
CG
Proud
INRA, UMR 1019 Nutrition Humaine, Centre de Clermont-Ferrand-Theix, F-63122 Saint Genès Champanelle, France.|Université Clermont 1, UFR Médecine, UMR 1019 Nutrition Humaine, Clermont-Ferrand, France.
Pierre
P
Fafournoux
D051701:Activating Transcription Factor 4 / Q000378:metabolism*; D000818:Animals; D001120:Arginine / Q000172:deficiency; D004622:Embryo, Mammalian / Q000166:cytology; D015852:Eukaryotic Initiation Factor-2 / Q000378:metabolism; D005347:Fibroblasts / Q000378:metabolism; D007930:Leucine / Q000172:deficiency*; D000076222:Mechanistic Target of Rapamycin Complex 1 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D051379:Mice; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D015398:Signal Transduction
D015852:Eukaryotic Initiation Factor-2; D051701:Activating Transcription Factor 4; D001120:Arginine; C070634:Eif2ak4 protein, mouse; D000076222:Mechanistic Target of Rapamycin Complex 1; D017346:Protein Serine-Threonine Kinases; D007930:Leucine