The general amino acid control pathway regulates mTOR and autophagy during serum/glutamine starvation.
The general amino acid control pathway regulates mTOR and autophagy during serum/glutamine starvation.
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DOI：
10.1083/jcb.201403009
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发表时间：
2014-07-21
期刊：
影响因子：
--
通讯作者：
Yu L
中科院分区：
文献类型：
--
作者：
Chen R;Zou Y;Mao D;Sun D;Gao G;Shi J;Liu X;Zhu C;Yang M;Ye W;Hao Q;Li R;Yu L
为了满足它们的代谢需要，饥饿的细胞首先激活自噬，但与一般氨基酸控制途径平行的激活增加了氨基酸摄取，导致mTOR的再激活和自噬的下调。生物体已经进化出复杂的机制来调节细胞内营养水平，以响应外源营养素的波动。在饥饿期间，细胞可以通过一般氨基酸控制（GAAC）途径增强氨基酸的摄取和合成，而非必需的细胞内容物则通过自噬进行回收。目前还不清楚这两种途径在应对饥饿时是如何协调的。在这里，我们表明，GAAC途径夫妇外源氨基酸的可用性与自噬。饥饿导致mTOR失活，然后激活自噬。同时，血清/谷氨酰胺饥饿激活GAAC途径，其上调氨基酸转运蛋白，导致氨基酸摄取增加。这提高了细胞内的氨基酸水平，进而重新激活mTOR并抑制自噬。转录激活因子4（GAAC途径中的主要转录因子）或SLC 7A 5（亮氨酸转运蛋白）的敲低导致mTOR再激活受损和更高水平的自噬。因此，GAAC途径通过在血清/谷氨酰胺饥饿期间调节氨基酸摄取和mTOR再活化来调节自噬。
To meet their metabolic needs, starved cells first activate autophagy, but activation in parallel of the general amino acid control pathway increases amino acid uptake, leading to reactivation of mTOR and down-regulation of autophagy. Organisms have evolved elaborate mechanisms to adjust intracellular nutrient levels in response to fluctuating availability of exogenous nutrients. During starvation, cells can enhance amino acid uptake and synthesis through the general amino acid control (GAAC) pathway, whereas nonessential cellular contents are recycled by autophagy. How these two pathways are coordinated in response to starvation is currently unknown. Here we show that the GAAC pathway couples exogenous amino acid availability with autophagy. Starvation caused deactivation of mTOR, which then activated autophagy. In parallel, serum/glutamine starvation activated the GAAC pathway, which up-regulated amino acid transporters, leading to increased amino acid uptake. This elevated the intracellular amino acid level, which in turn reactivated mTOR and suppressed autophagy. Knockdown of activating transcription factor 4, the major transcription factor in the GAAC pathway, or of SLC7A5, a leucine transporter, caused impaired mTOR reactivation and much higher levels of autophagy. Thus, the GAAC pathway modulates autophagy by regulating amino acid uptake and mTOR reactivation during serum/glutamine starvation.
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影响因子：
4.2
作者：
Fürst, P;Stehle, P
通讯作者：
Stehle, P
影响因子：
8
作者：
Rzymski, T.;Milani, M.;Harris, A. L.
通讯作者：
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影响因子：
14.9
作者：
B'chir W;Maurin AC;Carraro V;Averous J;Jousse C;Muranishi Y;Parry L;Stepien G;Fafournoux P;Bruhat A
通讯作者：
Bruhat A
影响因子：
23.9
作者：
Tang F;Barbacioru C;Bao S;Lee C;Nordman E;Wang X;Lao K;Surani MA
通讯作者：
Surani MA
影响因子：
56.9
作者：
Hao, SZ;Sharp, JW;Gietzen, DW
通讯作者：
Gietzen, DW