SAR1B senses leucine levels to regulate mTORC1 signalling
SAR1B senses leucine levels to regulate mTORC1 signalling
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SAR1B 感知亮氨酸水平来调节 mTORC1 信号传导
DOI：
10.1038/s41586-021-03768-w
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发表时间：
2021-07-21
期刊：
影响因子：
64.8
通讯作者：
Liu, Ying
中科院分区：
文献类型：
--
作者：
Chen, Jie;Ou, Yuhui;Liu, Ying
mTOR复合物1（mTORC 1）响应于氨基酸水平控制细胞生长。在这里，我们报告SAR 1B作为一个亮氨酸传感器，调节mTORC 1信号在响应细胞内水平的亮氨酸。在亮氨酸缺乏的条件下，SAR 1B通过物理靶向其激活剂GATOR 2来抑制mTORC 1。在亮氨酸充足的条件下，SAR 1B与亮氨酸结合，经历构象变化并与GATOR 2解离，这导致mTORC 1活化。SAR 1B-GATOR 2-mTORC 1信号传导在线虫中是保守的，并且在寿命调节中起作用。生物信息学分析显示，SAR 1B缺陷与肺癌的发生相关。SAR 1B及其副产物SAR 1A的沉默促进小鼠肺肿瘤的mTORC 1依赖性生长。我们的研究结果表明，SAR 1B是一种保守的亮氨酸传感器，在肺癌的发展中具有潜在的作用。
The mTOR complex 1 (mTORC1) controls cell growth in response to amino acid levels. Here we report SAR1B as a leucine sensor that regulates mTORC1 signalling in response to intracellular levels of leucine. Under conditions of leucine deficiency, SAR1B inhibits mTORC1 by physically targeting its activator GATOR2. In conditions of leucine sufficiency, SAR1B binds to leucine, undergoes a conformational change and dissociates from GATOR2, which results in mTORC1 activation. SAR1B–GATOR2–mTORC1 signalling is conserved in nematodes and has a role in the regulation of lifespan. Bioinformatic analysis reveals that SAR1B deficiency correlates with the development of lung cancer. The silencing of SAR1B and its paralogue SAR1A promotes mTORC1-dependent growth of lung tumours in mice. Our results reveal that SAR1B is a conserved leucine sensor that has a potential role in the development of lung cancer.