Effect of modulation of unfolded protein response pathway on dengue virus infection.

Abstract

The unfolded protein response (UPR) is a cascade of events that helps restoring cellular homeostasis under stressful conditions. It is activated when there is an imbalance in the protein load and protein folding capacity of the endoplasmic reticulum (ER) as a result of an increase in the naïve, unfolded, or misfolded protein content of the cell. Dengue virus (DENV) utilizes the host machinery to synthesize viral proteins and replicates in the cell. During DENV infection, up-regulation of viral proteins increases the protein pool of the cell, resulting in the induction of UPR pathway. In this study, we have tried to understand the consequence of UPR induction during DENV infection in human monocytic cells. To fulfill this objective, we have used VER-155008 (VER), a known inhibitor of the 78 kDa glucose-regulated protein (GRP78), which is the master regulator of the UPR pathway. After VER treatment, cells were infected with DENV, and the induction of the UPR elements and their downstream activation was studied by western blotting and RT-PCR analysis. Interestingly, inhibition of GRP78 via VER treatment led to the decreased expression of DENV envelope protein through the activation of the UPR elements, protein kinase-like ER resident kinase, activating transcription factor 6, and inositol-requiring enzyme 1 (IRE1), and then led to the activation of innate immune factors such as double-stranded RNA-activated protein kinase (PKR), interferon regulated factor 3 (IRF3), nuclear factor-κB (NF-κB) and interleukin 1β (IL-1β). This strategy may be used to decrease viral infection transiently. Thus UPR elements could be important therapeutic targets for decreasing DENV multiplication.