GSK-3β-dependent downregulation of γ-taxilin and αNAC merge to regulate ER stress responses.
GSK-3β-dependent downregulation of γ-taxilin and αNAC merge to regulate ER stress responses.
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DOI：
10.1038/cddis.2015.90
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发表时间：
2015-04-16
影响因子：
9
通讯作者：
Nakamura T
中科院分区：
文献类型：
--
作者：
Hotokezaka Y;Katayama I;van Leyen K;Nakamura T
导致内质网（ER）应激反应的信号通路尚未完全阐明。我们发现，糖原合成酶激酶3β（GSK-3β）依赖性下调γ-taxilin和新生多肽相关复合物α-亚基（αNAC）介导缺氧诱导的未折叠蛋白反应（UPRs）以及随后的凋亡和自噬途径。γ-taxilin或αNAC的降解足以在常氧细胞中启动UPR。然而，γ-taxilin和α-NAC启动的ER应激信号通路是不同的，触发不同的ER应激传感器并激活不同的下游通路。缺氧引起神经元细胞中GSK-3β依赖性tau蛋白过度磷酸化和裂解，但γ-紫杉醇消融仅诱导tau蛋白过度磷酸化，αNAC消融未诱导任何变化。值得注意的是，γ-紫杉烷和αNAC的下调发生在阿尔茨海默病患者的脑中。这些结果表明，GSK-3β依赖性下调γ-taxilin和αNAC，这两种不同激活UPR的蛋白，合并调节缺氧诱导的ER应激反应，并为神经退行性疾病的发病机制提供了新的见解。
The signaling pathway leading to the endoplasmic reticulum (ER) stress responses has not been fully elucidated. Here we showed that glycogen synthase kinase-3β (GSK-3β)-dependent downregulation of γ-taxilin and nascent polypeptide-associated complex α-subunit (αNAC) mediates hypoxia-induced unfolded protein responses (UPRs) and the subsequent apoptotic and autophagic pathways. The degradation of γ-taxilin or αNAC was sufficient to initiate UPRs in normoxic cells. However, the ER stress signaling pathways initiated by γ-taxilin or αNAC were distinct, triggering different ER stress sensors and activating different downstream pathways. Hypoxia caused GSK-3β-dependent tau hyperphosphorylation and cleavage in neuronal cells, but γ-taxilin ablation induced tau hyperphosphorylation alone and αNAC ablation induced neither changes. Notably, downregulation of γ-taxilin and αNAC occurs in the brain of patients with Alzheimer's disease. These results suggest that GSK-3β-dependent downregulation of γ-taxilin and αNAC, which differently activate the UPRs, merge to regulate hypoxia-induced ER stress responses and provide a new insight into the pathogenesis of neurodegenerative diseases.