DAP-kinase is a mediator of endoplasmic reticulum stress-induced caspase activation and autophagic cell death
DAP-kinase is a mediator of endoplasmic reticulum stress-induced caspase activation and autophagic cell death
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DOI：
10.1038/cdd.2008.121
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发表时间：
2008-12-01
影响因子：
12.4
通讯作者：
Kimchi, A.
中科院分区：
文献类型：
--
作者：
Gozuacik, D.;Bialik, S.;Kimchi, A.
对内质网（ER）稳态的破坏不能通过未折叠蛋白反应来纠正，从而激活细胞死亡。在这里，我们确定了死亡相关蛋白激酶（DAPk）作为一个重要组成部分，在内质网应激诱导的细胞死亡途径。保护DAPk-/-小鼠免受由注射ER应激诱导剂衣霉素引起的肾损伤。同样，在DAPk-/-原代成纤维细胞中，对ER应激诱导剂的细胞死亡反应降低。半胱天冬酶激活和自噬诱导，由ER应激激活并先于细胞死亡的事件，在DAPk无效细胞中显著减弱。值得注意的是，在这种细胞环境中，自噬作为第二种细胞杀伤机制，与细胞凋亡协同作用，因为当与半胱天冬酶-3耗尽组合时，Atg 5或Beclin 1从成纤维细胞中的耗尽显著保护免于ER应激诱导的死亡。我们进一步表明，内质网应激促进DAPk的催化活性，引起抑制性自磷酸化的丝氨酸（308）的PP 2A样磷酸酶的去磷酸化。因此，DAPk构成了ER应激信号传导的关键整合点，将这些信号传递到两个不同的方向，半胱天冬酶激活和自噬，导致细胞死亡。
Damage to endoplasmic reticulum (ER) homeostasis that cannot be corrected by the unfolded protein response activates cell death. Here, we identified death-associated protein kinase (DAPk) as an important component in the ER stress-induced cell death pathway. DAPk-/- mice are protected from kidney damage caused by injection of the ER stress-inducer tunicamycin. Likewise, the cell death response to ER stress-inducers is reduced in DAPk-/- primary fibroblasts. Both caspase activation and autophagy induction, events that are activated by ER stress and precede cell death, are significantly attenuated in the DAPk null cells. Notably, in this cellular setting, autophagy serves as a second cell killing mechanism that acts in concert with apoptosis, as the depletion of Atg5 or Beclin1 from fibroblasts significantly protected from ER stress-induced death when combined with caspase-3 depletion. We further show that ER stress promotes the catalytic activity of DAPk by causing dephosphorylation of an inhibitory autophosphorylation on Ser(308) by a PP2A-like phosphatase. Thus, DAPk constitutes a critical integration point in ER stress signaling, transmitting these signals into two distinct directions, caspase activation and autophagy, leading to cell death.