GCN2 sustains mTORC1 suppression upon amino acid deprivation by inducing Sestrin2

Mammalian cells possess two amino acid-sensing kinases: general control nonderepressible 2 (GCN2) and mechanistic target of rapamycin complex 1 (mTORC1). Their combined effects orchestrate cellular adaptation to amino acid levels, but how their activities are coordinated remains poorly understood. H...

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Bibliographic Details
Published in:Genes & development 2015-11, Vol.29 (22), p.2331-2336
Main Authors: Ye, Jiangbin, Palm, Wilhelm, Peng, Min, King, Bryan, Lindsten, Tullia, Li, Ming O, Koumenis, Constantinos, Thompson, Craig B
Format: Article
Language:English
Subjects:
Activating Transcription Factor 4 - genetics
Activating Transcription Factor 4 - metabolism
Amino Acids - metabolism
Animals
Cell Line
Cell Line, Tumor
Cell Survival - genetics
Gene Expression Regulation
HEK293 Cells
Humans
Lysosomes - metabolism
Mechanistic Target of Rapamycin Complex 1
Mice
Multiprotein Complexes - metabolism
Nuclear Proteins - genetics
Nuclear Proteins - metabolism
Protein-Serine-Threonine Kinases - metabolism
Research Communication
Signal Transduction
TOR Serine-Threonine Kinases - metabolism
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Summary:Mammalian cells possess two amino acid-sensing kinases: general control nonderepressible 2 (GCN2) and mechanistic target of rapamycin complex 1 (mTORC1). Their combined effects orchestrate cellular adaptation to amino acid levels, but how their activities are coordinated remains poorly understood. Here, we demonstrate an important link between GCN2 and mTORC1 signaling. Upon deprivation of various amino acids, activated GCN2 up-regulates ATF4 to induce expression of the stress response protein Sestrin2, which is required to sustain repression of mTORC1 by blocking its lysosomal localization. Moreover, Sestrin2 induction is necessary for cell survival during glutamine deprivation, indicating that Sestrin2 is a critical effector of GCN2 signaling that regulates amino acid homeostasis through mTORC1 suppression.
ISSN:0890-9369
1549-5477
DOI:10.1101/gad.269324.115