GCN2 contributes to mTORC1 inhibition by leucine deprivation through an ATF4 independent mechanism.
GCN2 contributes to mTORC1 inhibition by leucine deprivation through an ATF4 independent mechanism.
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DOI：
10.1038/srep27698
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发表时间：
2016-06-14
影响因子：
4.6
通讯作者：
Fafournoux P
中科院分区：
文献类型：
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作者：
Averous J;Lambert-Langlais S;Mesclon F;Carraro V;Parry L;Jousse C;Bruhat A;Maurin AC;Pierre P;Proud CG;Fafournoux P
众所周知，GCN 2和mTORC 1信号通路受氨基酸调节，并具有共同的功能，特别是控制翻译。氨基酸可用性对GCN 2活性的调节依赖于GCN 2在氨基酸缺乏时感知不带电tRNA水平增加的能力。相比之下，尽管最近在理解mTORC1的氨基酸调控方面取得了进展，但这一过程的关键方面仍未解决。特别是，虽然亮氨酸是众所周知的是一个有效的调节mTORC1的，这种氨基酸的传感和控制mTORC1活性的机制还没有很好地定义。我们的数据证实，GCN 2参与亮氨酸或精氨酸剥夺后mTORC 1的抑制。然而，单独激活GCN 2不足以抑制mTORC 1活性，表明亮氨酸和精氨酸通过其他机制发挥调节作用。虽然GCN 2参与mTORC 1抑制的初始步骤的机制涉及eIF2α的磷酸化，但我们表明它不依赖于下游转录因子ATF 4。这些数据表明GCN 2和eIF2α磷酸化在某些氨基酸控制mTORC 1中的新作用。
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.