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

Ying Ray Lee, Szu Han Kuo, Ching Yen Lin, Po Jung Fu, Yee-Shin Lin, Trai-Ming Yeh, Hsiao-Sheng Liu

Research output: Contribution to journalArticle

11 Citations (Scopus)

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.

Original languageEnglish
Article number489
JournalScientific reports
Volume8
Issue number1
DOIs
Publication statusPublished - 2018 Dec 1

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Virus Activation
Dengue Virus
Endoplasmic Reticulum Stress
Autophagy
Virus Diseases
Unfolded Protein Response
Endoplasmic Reticulum
Protein Unfolding
In Vitro Techniques
MAP Kinase Signaling System
Virus Replication
Heat-Shock Proteins
Viral Load

All Science Journal Classification (ASJC) codes

  • General

Cite this

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title = "Dengue virus-induced ER stress is required for autophagy activation, viral replication, and pathogenesis both in vitro and in vivo",
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.",
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Dengue virus-induced ER stress is required for autophagy activation, viral replication, and pathogenesis both in vitro and in vivo. / Lee, Ying Ray; Kuo, Szu Han; Lin, Ching Yen; Fu, Po Jung; Lin, Yee-Shin; Yeh, Trai-Ming; Liu, Hsiao-Sheng.

In: Scientific reports, Vol. 8, No. 1, 489, 01.12.2018.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Dengue virus-induced ER stress is required for autophagy activation, viral replication, and pathogenesis both in vitro and in vivo

AU - Lee, Ying Ray

AU - Kuo, Szu Han

AU - Lin, Ching Yen

AU - Fu, Po Jung

AU - Lin, Yee-Shin

AU - Yeh, Trai-Ming

AU - Liu, Hsiao-Sheng

PY - 2018/12/1

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