Division of Radiation Effects, Korea Institute of Radiological and Medical Sciences , Seoul.
Int J Radiat Biol. 2014 Apr;90(4):306-12. doi: 10.3109/09553002.2014.886793. Epub 2014 Mar 19.
Perturbations in protein folding induce endoplasmic reticulum (ER) stress, which elicits coordinated response, namely the unfolded protein response (UPR), to cope with the accumulation of misfolded proteins in ER. In this study, we characterized mechanisms underlying ionizing radiation (IR)-induced UPR signaling pathways.
We analyzed alterations in UPR signaling pathways in human umbilical vein endothelial cells (HUVEC) and human coronary artery endothelial cells (HCAEC) irradiated with 15 Gy IR.
IR selectively activated the eIF2α/ATF4 branch of the UPR signaling pathway, with no alterations in the IRE1 and ATF6 branches in HUVEC and HCAEC. Phosphorylation of PERK was enhanced in response to IR, and the IR-induced activation of the eIF2α/ATF4 signaling pathway was completely inhibited by PERK knockdown with siRNA. Surprisingly, chemical chaperones, which inhibit the formation of misfolded proteins and sequential protein aggregates to reduce ER stress, failed to prevent the IR-induced phosphorylation of PERK and the subsequent activation of the eIF2α/ATF4 signaling pathway.
PERK mediates the IR-induced selective activation of the eIF2α/ATF4 signaling pathway, and the IR-induced activation of PERK/eIF2α/ATF4 signaling in human vascular endothelial cells is independent of alterations in protein-folding homeostasis in the ER.
蛋白质折叠的改变会引起内质网（ER）应激，从而引发未折叠蛋白反应（UPR）的协调反应，以应对 ER 中错误折叠蛋白的积累。在这项研究中，我们研究了电离辐射（IR）诱导的 UPR 信号通路的机制。
我们分析了 15GyIR 照射的人脐静脉内皮细胞（HUVEC）和人冠状动脉内皮细胞（HCAEC）中 UPR 信号通路的改变。
IR 选择性地激活了 UPR 信号通路中的 eIF2α/ATF4 分支，而在 HUVEC 和 HCAEC 中，IRE1 和 ATF6 分支没有改变。PERK 的磷酸化增强了对 IR 的反应，而 PERK 敲低的 siRNA 完全抑制了 IR 诱导的 eIF2α/ATF4 信号通路的激活。令人惊讶的是，化学伴侣，抑制错误折叠蛋白的形成和连续的蛋白聚集体以减少 ER 应激，未能防止 IR 诱导的 PERK 磷酸化和随后的 eIF2α/ATF4 信号通路的激活。
PERK 介导了 IR 诱导的 eIF2α/ATF4 信号通路的选择性激活，而人血管内皮细胞中 PERK/eIF2α/ATF4 信号通路的 IR 诱导激活与 ER 中蛋白质折叠稳态的改变无关。
