Japanese encephalitis virus infection initiates endoplasmic reticulum stress and an unfolded protein response
Japanese encephalitis virus infection initiates endoplasmic reticulum stress and an unfolded protein response
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DOI：
10.1128/jvi.76.9.4162-4171.2002
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发表时间：
2002-05-01
影响因子：
5.4
通讯作者：
Lin, YL
中科院分区：
文献类型：
--
作者：
Su, HL;Liao, CL;Lin, YL
从酵母到哺乳动物的宿主细胞内质网（ER）的功能障碍可以触发未折叠蛋白反应（UPR）。这种功能障碍可能是由多种ER应激引起的，包括蛋白糖基化和钙失衡的抑制。为了科普ER应激，细胞可以依赖于UPR从ER向细胞核发送信号以刺激适当的细胞应答，包括诱导伴侣蛋白表达。在日本脑炎病毒（JEV）感染期间，ER的内腔迅速积累大量的病毒蛋白用于病毒子代的产生。在本研究中，我们证明了某些伴侣诱导，JEV感染触发成纤维细胞BHK-21细胞和神经元N18和NT-2细胞中的UPR，其中JEV导致细胞凋亡。相反，在JEV感染的耐药K562细胞中未观察到UPR。JEV感染还激活CHOP/GADD 153的表达，CHOP/GADD 153是一种独特的转录因子，通常由UPR诱导，并且似乎触发p38丝裂原活化蛋白激酶的激活，p38丝裂原活化蛋白激酶是CHOP的翻译后激活剂。异位执行CHOP表达增强JEV诱导的细胞凋亡，而治疗与p38特异性抑制剂，SB 203580，部分阻断JEV诱导的细胞凋亡。有趣的是，bcl-2过表达和用pancaspase抑制剂z-VAD-feptin处理抑制CHOP诱导并减少JEV诱导的凋亡，表明Bcl-2和caspase可能是CHOP的上游调节剂。因此，我们的研究结果表明，病毒诱导的内质网应激可能参与，通过p38依赖和CHOP介导的途径，在由JEV感染引发的凋亡过程。
The malfunctioning of the endoplasmic reticulum (ER) of cells in hosts ranging from yeast to mammals can trigger an unfolded protein response (UPR). Such malfunctioning can result from a variety of ER stresses, including the inhibition of protein glycosylation and calcium imbalance. To cope with ER stresses, cells may rely on the UPR to send a signal(s) from the ER to the nucleus to stimulate appropriate cellular responses, including induction of chaperone expression. During Japanese encephalitis virus (JEV) infection, the lumen of the ER rapidly accumulates substantial amounts of viral proteins for virus progeny production. In the present study, we demonstrate that as evidenced by certain chaperone inductions, JEV infection triggers the UPR in fibroblast BHK-21 cells and in neuronal N18 and NT-2 cells, in which JEV results in apoptotic cell death. By contrast, no UPR was observed in apoptosis-resistant K562 cells infected by JEV. JEV infection also activates expression of CHOP/GADD153, a distinctive transcription factor often induced by the UPR, and appears to trigger activation of p38 mitogen-activated protein kinase, a posttranslational activator of CHOP. Ectopic enforcement of CHOP expression enhanced JEV-induced apoptosis, whereas treatment with a p38-specific inhibitor, SB203580, partially blocked JEV-induced apoptosis. Interestingly, bcl-2 overexpression and treatment with a pancaspase inhibitor, z-VAD-fmk, inhibited CHOP induction and diminished JEV-induced apoptosis, suggesting that Bcl-2 and caspases could be the upstream regulators of CHOP. Our results thus suggest that virus-induced ER stress may participate, via p38-dependent and CHOP-mediated pathways, in the apoptotic process triggered by JEV infection.