The general amino acid control pathway regulates mTOR and autophagy during serum/glutamine starvation
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 cellula...
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| Published in | The Journal of cell biology Vol. 206; no. 2; pp. 173 - 182 |
|---|---|
| Main Authors | , , , , , , , , , , , , |
| Format | Journal Article |
| Language | English |
| Published |
United States
Rockefeller University Press
21.07.2014
The Rockefeller University Press |
| Subjects | |
| Online Access | Get full text |
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| Abstract | 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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| AbstractList | 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. 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. 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.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. |
| Author | Shi, Jingwen Hao, Qianqian Yu, Li Li, Ruiqiang Gao, Guanguang Ye, Wanlu Chen, Rui Sun, Daxiao Mao, Dongxue Zhu, Chen Zou, Yilong Yang, Mingyu Liu, Xiaoqing |
| AuthorAffiliation | 1 State Key Laboratory of Biomembrane and Membrane Biotechnology, Tsinghua University-Peking University Joint Center for Life Sciences, School of Life Sciences, Tsinghua University, Beijing 100084, China 2 Biodynamics Optical Imaging Center, Peking University, Beijing 100871, China 3 Beijing Amino Medical Research Company, Beijing 100084, China |
| AuthorAffiliation_xml | – name: 1 State Key Laboratory of Biomembrane and Membrane Biotechnology, Tsinghua University-Peking University Joint Center for Life Sciences, School of Life Sciences, Tsinghua University, Beijing 100084, China – name: 3 Beijing Amino Medical Research Company, Beijing 100084, China – name: 2 Biodynamics Optical Imaging Center, Peking University, Beijing 100871, China |
| Author_xml | – sequence: 1 givenname: Rui surname: Chen fullname: Chen, Rui – sequence: 2 givenname: Yilong surname: Zou fullname: Zou, Yilong – sequence: 3 givenname: Dongxue surname: Mao fullname: Mao, Dongxue – sequence: 4 givenname: Daxiao surname: Sun fullname: Sun, Daxiao – sequence: 5 givenname: Guanguang surname: Gao fullname: Gao, Guanguang – sequence: 6 givenname: Jingwen surname: Shi fullname: Shi, Jingwen – sequence: 7 givenname: Xiaoqing surname: Liu fullname: Liu, Xiaoqing – sequence: 8 givenname: Chen surname: Zhu fullname: Zhu, Chen – sequence: 9 givenname: Mingyu surname: Yang fullname: Yang, Mingyu – sequence: 10 givenname: Wanlu surname: Ye fullname: Ye, Wanlu – sequence: 11 givenname: Qianqian surname: Hao fullname: Hao, Qianqian – sequence: 12 givenname: Ruiqiang surname: Li fullname: Li, Ruiqiang – sequence: 13 givenname: Li surname: Yu fullname: Yu, Li |
| BackLink | https://www.ncbi.nlm.nih.gov/pubmed/25049270$$D View this record in MEDLINE/PubMed |
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| SubjectTerms | Activating Transcription Factor 4 - genetics Activating Transcription Factor 4 - metabolism Activating Transcription Factor 4 - physiology Amino acids Amino Acids - metabolism Animals Autophagy Cell Line Cellular biology Gene Expression Regulation Gene Knockdown Techniques Glutamine - metabolism Homeostasis Large Neutral Amino Acid-Transporter 1 - genetics Large Neutral Amino Acid-Transporter 1 - metabolism Nutrient availability Proteins Rats Starvation TOR Serine-Threonine Kinases - metabolism |
| Title | The general amino acid control pathway regulates mTOR and autophagy during serum/glutamine starvation |
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