GCN2 sustains mTORC1 suppression upon amino acid deprivation by inducing Sestrin2

被引：269

作者：

Ye, Jiangbin ^{[1
]}

Palm, Wilhelm ^{[1
]}

Peng, Min ^{[2
]}

King, Bryan ^{[1
]}

Lindsten, Tullia ^{[2
]}

Li, Ming O. ^{[2
]}

Koumenis, Constantinos ^{[3
]}

Thompson, Craig B. ^{[1
]}

机构：

[1] Mem Sloan Kettering Canc Ctr, Canc Biol & Genet Program, New York, NY 10065 USA

[2] Mem Sloan Kettering Canc Ctr, Immunol Program, New York, NY 10065 USA

[3] Univ Penn, Perelman Sch Med, Dept Radiat Oncol, Philadelphia, PA 19104 USA

来源：

GENES & DEVELOPMENT | 2015年 / 29卷 / 22期

基金：

美国国家卫生研究院;

关键词：

GCN2; mTORC1; Sestrin; amino acid deprivation; P70; S6; KINASE; TRANSFER-RNA; RAG GTPASES; TRANSLATIONAL CONTROL; PROTEIN-SYNTHESIS; ACTIVATION; PHOSPHORYLATION; UPSTREAM; PATHWAY; DISSOCIATION;

D O I：

10.1101/gad.269324.115

中图分类号：

Q2 [细胞生物学];

学科分类号：

071013 [干细胞生物学];

摘要：

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.

引用

页码：2331 / 2336

页数：6

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