Endoplasmic reticulum (ER) stress induced by a neurovirulent mouse retrovirus is associated with prolonged BiP binding and retention of a viral protein in the ER
Endoplasmic reticulum (ER) stress induced by a neurovirulent mouse retrovirus is associated with prolonged BiP binding and retention of a viral protein in the ER
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DOI：
10.1074/jbc.m403304200
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发表时间：
2004-08-06
影响因子：
4.8
通讯作者：
Portis, JL
中科院分区：
文献类型：
--
作者：
Dimcheff, DE;Faasse, MA;Portis, JL
一些小鼠逆转录病毒引起海绵状神经退行性疾病，其病理表现与传染性海绵状脑病相似。这些“海绵状逆转录病毒”的神经毒力是由它们各自的包膜蛋白序列决定的，尽管神经毒性的机制尚不清楚。我们研究了一种名为FrCas(E)的高度神经毒力病毒，它会导致这种疾病的快速发展。最近，在感染FrCas(E)的小鼠大脑中检测到内质网(ER)应激的转录标志物在临床前的早期阶段。相比之下，在感染了携带不同包膜基因的无毒病毒F43的小鼠中没有观察到内质网应激，这表明内质网应激在疾病发病机制中发挥了作用。在这里，我们在NIH3T3细胞中研究了这种细胞应激反应的原因。F43的包膜蛋白与主要的内质网伴侣蛋白Bip短暂结合，并通过分泌途径正常加工。相反，FrCasE的包膜蛋白与Bip结合的时间较长，保留在内质网中，并被蛋白酶体降解。此外，通过ER质量控制途径接触FrCasE包膜蛋白导致该蛋白在NIH3T3细胞和感染小鼠脑中的稳态水平低于F43。因此，FrCasE诱导的内质网应激似乎是由其病毒包膜蛋白的低效折叠启动的，这表明该病毒引起的神经退行性疾病是一种蛋白质错误折叠障碍。
Some murine retroviruses cause a spongiform neurodegenerative disease exhibiting pathology resembling that observed in transmissible spongiform encephalopathies. The neurovirulence of these "spongiogenic retroviruses" is determined by the sequence of their respective envelope proteins, although the mechanisms of neurotoxicity are not understood. We have studied a highly neurovirulent virus called FrCas(E) that causes a rapidly progressive form of this disease. Recently, transcriptional markers of endoplasmic reticulum ( ER) stress were detected during the early preclinical period in the brains of FrCas(E)-infected mice. In contrast, ER stress was not observed in mice infected with an avirulent virus, F43, which carries a different envelope gene, suggesting a role for ER stress in disease pathogenesis. Here we have examined in NIH 3T3 cells the cause of this cellular stress response. The envelope protein of F43 bound BiP, a major ER chaperone, transiently and was processed normally through the secretory pathway. In contrast, the envelope protein of FrCasE bound to BiP for a prolonged period, was retained in the ER, and was degraded by the proteasome. Furthermore, engagement of the FrCasE envelope protein by ER quality control pathways resulted in decreased steady-state levels of this protein, relative to that of F43, both in NIH 3T3 cells and in the brains of infected mice. Thus, the ER stress induced by FrCasE appears to be initiated by inefficient folding of its viral envelope protein, suggesting that the neurodegenerative disease caused by this virus represents a protein misfolding disorder.