Division of Infectious Diseases and Vaccinology, School of Public Health, and Graduate Group in Microbiology, Department of Plant and Microbial Biology, University of California, Berkeley, California 94720-7354, USA.
J Biol Chem. 2011 Apr 22;286(16):14226-36. doi: 10.1074/jbc.M111.222703. Epub 2011 Mar 8.
Flaviviruses, such as dengue virus (DENV), depend on the host endoplasmic reticulum for translation, replication, and packaging of their genomes. Here we report that DENV-2 infection modulates the unfolded protein response in a time-dependent manner. We show that early DENV-2 infection triggers and then suppresses PERK-mediated eIF2α phosphorylation and that in mid and late DENV-2 infection, the IRE1-XBP1 and ATF6 pathways are activated, respectively. Activation of IRE1-XBP1 correlated with induction of downstream targets GRP78, CHOP, and GADD34. Furthermore, induction of CHOP did not induce apoptotic markers, such as suppression of anti-apoptotic protein Bcl-2, activation of caspase-9 or caspase-3, and cleavage of poly(ADP-ribose) polymerase. Finally, we show that DENV-2 replication is affected in PERK(-/-) and IRE1(-/-) mouse embryo fibroblasts when compared with wild-type mouse embryo fibroblasts. These results demonstrate that time-dependent activation of the unfolded protein response by DENV-2 can override inhibition of translation, prevent apoptosis, and prolong the viral life cycle.
黄病毒，如登革热病毒（DENV），依赖于宿主内质网进行其基因组的翻译、复制和包装。在这里，我们报告 DENV-2 感染以时间依赖性方式调节未折叠蛋白反应。我们表明，早期 DENV-2 感染触发并随后抑制 PERK 介导的 eIF2α磷酸化，而在中晚期 DENV-2 感染中，IRE1-XBP1 和 ATF6 途径分别被激活。IRE1-XBP1 的激活与下游靶标 GRP78、CHOP 和 GADD34 的诱导相关。此外，CHOP 的诱导不会诱导凋亡标志物，例如抗凋亡蛋白 Bcl-2 的抑制、半胱天冬酶-9 或半胱天冬酶-3 的激活以及多聚（ADP-核糖）聚合酶的切割。最后，我们表明与野生型鼠胚胎成纤维细胞相比，DENV-2 复制在 PERK(-/-)和 IRE1(-/-)鼠胚胎成纤维细胞中受到影响。这些结果表明，DENV-2 时间依赖性激活未折叠蛋白反应可以克服翻译抑制、防止细胞凋亡并延长病毒生命周期。
