| The cellular unfolded protein response (UPR) adapts the cell to stress and increases the endoplasmic reticulum (ER) protein-folding capacity. Dengue virus (DENV) and other members of the Flaviviridae family are ER-tropic viruses that depend upon the host ER to translate, replicate and package their genomes. In this study, we report that DENV2 infection activates and/or suppresses the three branches of the UPR in a time-dependent manner. We show that early in infection, DENV2 exploits the host integrated stress response (ISR), the translational component of the UPR, by triggering and then suppressing PERK-mediated eIF2alpha-phosphorylation. Additionally, we demonstrate that in mid- and late-infection, DENV2 activates the IRE1 and ATF6 pathways, respectively, and leads to the induction of downstream targets, GRP78, CHOP and GADD34, that prevent apoptosis and prolong the viral life cycle. Together, our data indicate how the DENV life cycle has evolved to take advantage of the cellular UPR. |
