Abstract
Dengue virus (DENV) utilizes the endoplasmic reticulum (ER) for replication and assembling. Accumulation of unfolded proteins in the ER lumen leads to ER stress and unfolded protein response (UPR). Three branches of UPRs temporally modulated DENV infection. Moreover, ER stress can also induce autophagy. DENV infection induces autophagy which plays a promotive role in viral replication has been reported. However, the role of ER stress in DENV-induced autophagy, viral titer, and pathogenesis remain unclear. Here, we reveal that ER stress and its downstream UPRs are indispensable for DENV-induced autophagy in various human cells. We demonstrate that PERK-eIF2α and IRE1α-JNK signaling pathways increased autophagy and viral load after DENV infection. However, ATF6-related pathway showed no effect on autophagy and viral replication. IRE1α-JNK downstream molecule Bcl-2 was phosphorylated by activated JNK and dissociated from Beclin 1, which playing a critical role in autophagy activation. These findings were confirmed as decreased viral titer, attenuated disease symptoms, and prolonged survival rate in the presence of JNK inhibitor in vivo. In summary, we are the first to reveal that DENV2-induced ER stress increases autophagy activity, DENV replication, and pathogenesis through two UPR signaling pathways both in vitro and in vivo.
Highlights
Dengue virus (DENV) contains four serotypes (DENV1 to DENV4)
We found that knockout of ATG5 gene showed no effect on DENV2 infection induced GRP78 expression (Fig. 1B), suggesting that autophagy progression is not at the up-stream of DENV2-induced endoplasmic reticulum (ER) stress
The result showed that blocking ER stress decreased the levels of GRP78, LC3-II as well as viral replication demonstrated by Western blotting and plaque assay (Fig. 1D and E)
Summary
DENV contains four serotypes (DENV1 to DENV4). DENV infection may cause diseases from mild dengue fever to severe syndromes of dengue shock syndrome (DSS) and dengue hemorrhagic fever (DHF). Three distinct pathways including Protein kinase-like endoplasmic reticulum kinase (PERK), inositol-requiring protein-1α (IRE1α), and activating transcription factor-6 (ATF6) have been reported to be the downstream mediators of UPR signaling under ER stress. These pathways are inactivated by binding with the chaperone protein GRP78/Bip under normal conditions. Activating transcription factor 4 (ATF4) is the linker between PERK and apoptosis or autophagy process, and is essential for the up-regulation of many ER stress-related genes including autophagy related protein (ATG12) and CHOP that participates in autophagy induction[8,9]. We investigate the pathways and the mechanisms between DENV-triggered ER stress and autophagy as well as the effects on viral replication and pathogenesis in vivo
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