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Sci Rep. 2018 Jan 11;8(1):489. doi: 10.1038/s41598-017-18909-3.

Dengue virus-induced ER stress is required for autophagy activation, viral replication, and pathogenesis both in vitro and in vivo.

Author information

1
Department of Medical Research, Chiayi Christian Hospital, 600, Chiayi, Taiwan.
2
Department of Microbiology and Immunology, College of Medicine, National Cheng Kung University, 701, Tainan, Taiwan.
3
Department of Medical Laboratory, Science and Biotechnology, College of Medicine, National Cheng Kung University, 701, Tainan, Taiwan.
4
Department of Microbiology and Immunology, College of Medicine, National Cheng Kung University, 701, Tainan, Taiwan. a713@mail.ncku.edu.tw.

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.

PMID:
29323257
PMCID:
PMC5765116
DOI:
10.1038/s41598-017-18909-3
[Indexed for MEDLINE]
Free PMC Article

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