An mTORC1-Mdm2-Drosha axis for miRNA biogenesis in response to glucose- and amino acid-deprivation.
An mTORC1-Mdm2-Drosha axis for miRNA biogenesis in response to glucose- and amino acid-deprivation.
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DOI：
10.1016/j.molcel.2014.12.034
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发表时间：
2015-02-19
期刊：
影响因子：
16
通讯作者：
Zheng P
中科院分区：
文献类型：
--
作者：
Ye P;Liu Y;Chen C;Tang F;Wu Q;Wang X;Liu CG;Liu X;Liu R;Liu Y;Zheng P
mTOR感测营养和能量状态以调节细胞存活和代谢以响应环境变化。令人惊讶的是，靶向突变的Tsc 1，一个负调控mTORC 1，导致广泛减少的miRNA由于Drosha降解。相反，mTORC 1的重要组成部分Raptor的靶向突变增加了miRNA的生物合成。mTOR激活增加了Mdm 2的表达，由此将其鉴定为Drosha必需且足够的泛素E3连接酶。Drosha由营养和能量剥夺诱导，并赋予对葡萄糖剥夺的抵抗力。使用miRNA文库的高通量筛选，我们鉴定了4种保护细胞免受葡萄糖剥夺诱导的凋亡所必需且足够的miRNA。葡萄糖通过mTORC 1-MDM 2- Drosha轴调控这些miRNA。总之，我们的数据揭示了哺乳动物细胞中的mTOR-Mdm 2-Drosha途径，该途径广泛调节miRNA生物合成，作为对细胞环境改变的响应。
mTOR senses nutrient and energy status to regulate cell survival and metabolism in response to environmental changes. Surprisingly, targeted mutation of Tsc1, a negative regulator of mTORC1, caused a broad reduction in miRNAs due to Drosha degradation. Conversely, targeted mutation of Raptor, an essential component of mTORC 1, increased miRNA biogenesis. mTOR activation increased expression of Mdm2, which is hereby identified as the necessary and sufficient ubiquitin E3 ligase for Drosha. Drosha was induced by nutrient and energy deprivation and conferred resistance to glucose deprivation. Using a high throughput screen of a miRNA library, we identified 4 miRNAs that were necessary and sufficient to protect cells against glucose deprivation-induced apoptosis. These miRNA was regulated by glucose through the mTORC1-MDM2- Drosha axis. Taken together, our data reveal an mTOR-Mdm2-Drosha pathway in mammalian cells that broadly regulates miRNA biogenesis as a response to alteration in cellular environment.