Expression of the hyperphosphorylated tau attenuates ER stress-induced apoptosis with upregulation of unfolded protein response
Expression of the hyperphosphorylated tau attenuates ER stress-induced apoptosis with upregulation of unfolded protein response
复制标题
DOI：
10.1007/s10495-012-0744-z
复制
发表时间：
2012-10-01
期刊：
影响因子：
7.2
通讯作者：
Wang, Jian-Zhi
中科院分区：
文献类型：
--
作者：
Liu, Xin-An;Song, Jie;Wang, Jian-Zhi
阿尔茨海默病(AD)的神经功能障碍可能与内质网(ER)应激和未折叠蛋白反应(UPR)缺陷有关。为了探讨tau蛋白过度磷酸化是否在内质网应激诱导的细胞活性改变中起作用，我们建立了稳定表达人tau蛋白的细胞系(HEK293/tau)或载体(HEK293/vec)，并用内质网应激诱导剂thapsigargin(TG)处理细胞。我们观察到HEK293/tau细胞比HEK293/vec细胞对TG诱导的细胞凋亡具有更强的抵抗力，重要的是，Thr205和Thr231位点tau磷酸化的时间依赖性增加与细胞凋亡的抑制呈正相关。我们还观察到，tau的表达上调了perk、eIF2和IRE1的磷酸化，增加了ATF6和ATF4的切割。其他内质网应激诱导剂，包括星形孢子素、喜树碱和过氧化氢处理的HEK293/tau细胞中也检测到UPR的增强，同时也显示出抑制细胞凋亡的作用。我们的结果提示tau的过度磷酸化可以减轻内质网应激诱导的细胞凋亡，其机制可能与上调UPR系统有关。
The neural dysfunction in Alzheimer's disease (AD) could arise from endoplasmic reticulum (ER) stress and deficits of the unfolded protein response (UPR). To explore whether tau hyperphosphorylation, a hallmark of AD brain pathologies, plays a role in ER stress-induced alterations of cell viability, we established cell lines with stable expression of human tau (HEK293/tau) or the vector (HEK293/vec) and treated the cells with thapsigargin (TG), an ER stress inducer. We observed that the HEK293/tau cells were more resistant than the HEK293/vec cells to the TG-induced apoptosis, importantly, a time dependent increase of tau phosphorylation at Thr205 and Thr231 sites was positively correlated with the inhibition of apoptosis. We also observed that expression of tau upregulated phosphorylation of PERK, eIF2 and IRE1 with an increased cleavage of ATF6 and ATF4. The potentiation of UPR was also detected in HEK293/tau cells treated with other ER stress inducers, including staurosporine, camptothecin and hydrogen peroxide, in which a suppressed apoptosis was also shown. Our data suggest that tau hyperphosphorylation could attenuate the ER stress-induced apoptosis with the mechanism involving upregulation of UPR system.