Inhibition of mTORC1 by Astrin and Stress Granules Prevents Apoptosis in Cancer Cells
Inhibition of mTORC1 by Astrin and Stress Granules Prevents Apoptosis in Cancer Cells
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DOI：
10.1016/j.cell.2013.07.031
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发表时间：
2013-08-15
期刊：
影响因子：
64.5
通讯作者：
Baumeister, Ralf
中科院分区：
文献类型：
--
作者：
Thedieck, Kathrin;Holzwarth, Birgit;Baumeister, Ralf
哺乳动物雷帕霉素复合体靶标1(MTORC1)在代谢信号的作用下控制生长和存活。氧化应激通过抑制性和刺激性输入影响mTORC1。虽然TSC1-TSC2的下调在氧化应激时激活了mTORC1，但mTORC1抑制的分子机制仍不清楚。在这里，我们认为Astrin是细胞应激反应中一个重要的负性mTORC1调节因子。在应激时，Astrin抑制mTORC1的结合，并将mTORC1成分猛禽招募到应激颗粒(SGS)，从而防止mTORC1过度激活诱导的细胞凋亡。反过来，平衡的mTORC1活性使应激因子得以表达。通过将Astrin确定为mTORC1、SG组装和应激反应之间的直接分子联系，我们建立了mTORC1在应激时抑制和激活的统一模型。重要的是，我们发现在癌细胞中，应激过程中的细胞凋亡抑制依赖于天冬氨酸。Astrin在肿瘤中频繁上调，是一个潜在的临床相关靶点，可使肿瘤对细胞凋亡敏感。
Mammalian target of rapamycin complex 1 (mTORC1) controls growth and survival in response to metabolic cues. Oxidative stress affects mTORC1 via inhibitory and stimulatory inputs. Whereas downregulation of TSC1-TSC2 activates mTORC1 upon oxidative stress, the molecular mechanism of mTORC1 inhibition remains unknown. Here, we identify astrin as an essential negative mTORC1 regulator in the cellular stress response. Upon stress, astrin inhibits mTORC1 association and recruits the mTORC1 component raptor to stress granules (SGs), thereby preventing mTORC1-hyperactivation-induced apoptosis. In turn, balanced mTORC1 activity enables expression of stress factors. By identifying astrin as a direct molecular link between mTORC1, SG assembly, and the stress response, we establish a unifying model of mTORC1 inhibition and activation upon stress. Importantly, we show that in cancer cells, apoptosis suppression during stress depends on astrin. Being frequently upregulated in tumors, astrin is a potential clinically relevant target to sensitize tumors to apoptosis.