Sestrin2 is induced by glucose starvation via the unfolded protein response and protects cells from non-canonical necroptotic cell death.
Sestrin2 is induced by glucose starvation via the unfolded protein response and protects cells from non-canonical necroptotic cell death.
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DOI：
10.1038/srep22538
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发表时间：
2016-03-02
影响因子：
4.6
通讯作者：
Budanov AV
中科院分区：
文献类型：
--
作者：
Ding B;Parmigiani A;Divakaruni AS;Archer K;Murphy AN;Budanov AV
Sestrin2 是应激反应蛋白家族的成员，它通过抗氧化活性和哺乳动物雷帕霉素蛋白激酶 (mTOR) 靶标的调节来控制细胞活力。 Sestrin2 是由不同的应激损伤诱导的，这些应激损伤会减少 ATP 的产生并在细胞中诱导能量应激。葡萄糖是通过糖酵解和线粒体呼吸产生 ATP 以及内质网 (ER) 和高尔基体中新合成蛋白质糖基化的关键底物。因此，葡萄糖饥饿会导致能量缺乏和内质网应激激活，进而引发未折叠蛋白反应（UPR）。在这里，我们证明 UPR 通过 ATF4 和 NRF2 转录因子诱导 Sestrin2，并证明 Sestrin2 可以保护细胞免受葡萄糖饥饿诱导的细胞死亡。 Sestrin2 失活使细胞对坏死性细胞死亡敏感，这种死亡与 ATP 水平下降相关，并且可以被 Necrostatin 7 抑制。我们提出 Sestrin2 通过调节线粒体稳态来保护细胞免受葡萄糖饥饿诱导的细胞死亡。
Sestrin2 is a member of a family of stress responsive proteins, which controls cell viability via antioxidant activity and regulation of the mammalian target of rapamycin protein kinase (mTOR). Sestrin2 is induced by different stress insults, which diminish ATP production and induce energetic stress in the cells. Glucose is a critical substrate for ATP production utilized via glycolysis and mitochondrial respiration as well as for glycosylation of newly synthesized proteins in the endoplasmic reticulum (ER) and Golgi. Thus, glucose starvation causes both energy deficiency and activation of ER stress followed by the unfolding protein response (UPR). Here, we show that UPR induces Sestrin2 via ATF4 and NRF2 transcription factors and demonstrate that Sestrin2 protects cells from glucose starvation-induced cell death. Sestrin2 inactivation sensitizes cells to necroptotic cell death that is associated with a decline in ATP levels and can be suppressed by Necrostatin 7. We propose that Sestrin2 protects cells from glucose starvation-induced cell death via regulation of mitochondrial homeostasis.