title: The general amino acid control pathway regulates mTOR and autophagy during serum/glutamine starvation.
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.
authors: 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.
authors: Rui
authors: R
authors: Chen
authors: 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.
authors: Yilong
authors: Y
authors: Zou
authors: 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.
authors: Dongxue
authors: D
authors: Mao
authors: 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.
authors: Daxiao
authors: D
authors: Sun
authors: 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.
authors: Guanguang
authors: G
authors: Gao
authors: 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.
authors: Jingwen
authors: J
authors: Shi
authors: 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.
authors: Xiaoqing
authors: X
authors: Liu
authors: 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.
authors: Chen
authors: C
authors: Zhu
authors: Biodynamics Optical Imaging Center, Peking University, Beijing 100871, China.
authors: Mingyu
authors: M
authors: Yang
authors: Biodynamics Optical Imaging Center, Peking University, Beijing 100871, China.
authors: Wanlu
authors: W
authors: Ye
authors: Beijing Amino Medical Research Company, Beijing 100084, China.
authors: Qianqian
authors: Q
authors: Hao
authors: Biodynamics Optical Imaging Center, Peking University, Beijing 100871, China liyulab@mail.tsinghua.edu.cn.
authors: Ruiqiang
authors: R
authors: Li
authors: 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 liyulab@mail.tsinghua.edu.cn.
authors: Li
authors: L
authors: Yu
mesh_terms: D051701:Activating Transcription Factor 4 / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D000596:Amino Acids / Q000378:metabolism*; D000818:Animals; D001343:Autophagy; D002460:Cell Line; D005786:Gene Expression Regulation; D055785:Gene Knockdown Techniques; D005973:Glutamine / Q000378:metabolism; D006706:Homeostasis; D027283:Large Neutral Amino Acid-Transporter 1 / Q000235:genetics / Q000378:metabolism; D051381:Rats; D013217:Starvation; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*
chemical_list: D000596:Amino Acids; D027283:Large Neutral Amino Acid-Transporter 1; D005973:Glutamine; D051701:Activating Transcription Factor 4; D058570:TOR Serine-Threonine Kinases