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J Biol Chem. 2011 Apr 22;286(16):14226-36. doi: 10.1074/jbc.M111.222703. Epub 2011 Mar 8.

Dengue virus modulates the unfolded protein response in a time-dependent manner.

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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.


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.

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