Neuroprotective actions of PIKE-L by inhibition of SET proteolytic degradation by asparagine endopeptidase
Neuroprotective actions of PIKE-L by inhibition of SET proteolytic degradation by asparagine endopeptidase
复制标题
DOI：
10.1016/j.molcel.2008.02.017
复制
发表时间：
2008-03-28
期刊：
影响因子：
16
通讯作者：
Ye, Keqiang
中科院分区：
文献类型：
--
作者：
Liu, Zhixue;Jang, Sung-Wuk;Ye, Keqiang
缺血和癫痫发作会导致神经元过度兴奋，从而导致脑酸中毒和神经元细胞死亡。然而，酸化触发神经元损伤的分子机制尚未完全了解。在这里，我们表明天冬酰胺内肽酶（AEP）在酸性条件下被激活，切割DNA酶抑制剂SET，并引发大脑中的DNA损伤，而这种损伤被PIKE-L抑制。SET是半胱天冬酶的底物，它被酸性胞浆提取物切割，与半胱天冬酶的激活无关。酸性细胞提取物的分级分离产生SET切割所需的AEP。我们发现，红藻氨酸引起AEP激活和SET切割在N175，触发DNA切口在野生型，但不是AEP无效，小鼠。PIKE-L能与SET结合，并阻止AEP降解SET，从而抵抗神经元细胞死亡。此外，AEP还介导脑卒中引起的SET裂解和细胞死亡。因此，AEP可能是神经兴奋性中毒或缺血时酸中毒激活的蛋白酶之一，从而引起神经元损伤。
Ischemia and seizure cause excessive neuronal excitation that is associated with brain acidosis and neuronal cell death. However, the molecular mechanism of acidification-triggered neuronal injury is incompletely understood. Here, we show that asparagine endopeptidase (AEP) is activated under acidic condition, cuts SET, an inhibitor of DNase, and triggers DNA damage in brain, which is inhibited by PIKE-L. SET, a substrate of caspases, was cleaved by acidic cytosolic extract independent of caspase activation. Fractionation of the acidic cellular extract yielded AEP that is required for SET cleavage. We found that kainate provoked AEP activation and SET cleavage at N175, triggering DNA nicking in wild-type, but not AEP null, mice. PIKE-L strongly bound SET and prevented its degradation by AEP, leading to resistance of neuronal cell death. Moreover, AEP also mediated stroke-provoked SET cleavage and cell death in brain. Thus, AEP might be one of the proteinases activated by acidosis triggering neuronal injury during neuroexcitotoxicity or ischemia.