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Viruses 2017, 9(9), 262; doi:10.3390/v9090262

PERK Signal-Modulated Protein Translation Promotes the Survivability of Dengue 2 Virus-Infected Mosquito Cells and Extends Viral Replication

1
Graduate Institute of Biomedical Sciences, Chang Gung University, Kwei-San, Tao-Yuan 33332, Taiwan
2
Department of Public Health and Parasitology, Chang Gung University, Kwei-San, Tao-Yuan 33332, Taiwan
3
Environmental Health Department, Banjarnegara Polytechnic, Central Java 53482, Indonesia
4
Molecular Infectious Disease Research Center, Chang Gung Memorial Hospital, Kwei-San, Tao-Yuan 33332, Taiwan
5
Division of Pediatric Infectious Diseases, Department of Pediatrics, Chang Gung Children’s Hospital, Chang Gung University College of Medicine, Kwei-San, Tao-Yuan 33305, Taiwan
6
Department of Microbiology and Immunology, Chang Gung University, Kwei-San, Tao-Yuan 33332, Taiwan
*
Authors to whom correspondence should be addressed.
Received: 14 August 2017 / Revised: 15 September 2017 / Accepted: 17 September 2017 / Published: 20 September 2017
(This article belongs to the Special Issue Viral Subversion of Transcriptional Control)
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Abstract

Survival of mosquitoes from dengue virus (DENV) infection is a prerequisite of viral transmission to the host. This study aimed to see how mosquito cells can survive the infection during prosperous replication of the virus. In C6/36 cells, global protein translation was shut down after infection by DENV type 2 (DENV2). However, it returned to a normal level when infected cells were treated with an inhibitor of the protein kinase RNA (PKR)-like ER kinase (PERK) signaling pathway. Based on a 7-Methylguanosine 5′-triphosphate (m7GTP) pull-down assay, the eukaryotic translation initiation factor 4F (eIF4F) complex was also identified in DENV2-infected cells. This suggests that most mosquito proteins are synthesized via canonical cap-dependent translation. When the PERK signal pathway was inhibited, both accumulation of reactive oxygen species and changes in the mitochondrial membrane potential increased. This suggested that ER stress response was alleviated through the PERK-mediated shutdown of global proteins in DENV2-infected C6/36 cells. In the meantime, the activities of caspases-9 and -3 and the apoptosis-related cell death rate increased in C6/36 cells with PERK inhibition. This reflected that the PERK-signaling pathway is involved in determining cell survival, presumably by reducing DENV2-induced ER stress. Looking at the PERK downstream target, α-subunit of eukaryotic initiation factor 2 (eIF2α), an increased phosphorylation status was only shown in infected C6/36 cells. This indicated that recruitment of ribosome binding to the mRNA 5′-cap structure could have been impaired in cap-dependent translation. It turned out that shutdown of cellular protein translation resulted in a pro-survival effect on mosquito cells in response to DENV2 infection. As synthesis of viral proteins was not affected by the PERK signal pathway, an alternate mode other than cap-dependent translation may be utilized. This finding provides insights into elucidating how the PERK signal pathway modulates dynamic translation of proteins and helps mosquito cells survive continuous replication of the DENV2. It was ecologically important for virus amplification in mosquitoes and transmission to humans. View Full-Text
Keywords: dengue 2 virus; mosquito cells; PERK signaling pathway; eIF2α phosphorylation; protein translation; ER stress alleviation; cell survival dengue 2 virus; mosquito cells; PERK signaling pathway; eIF2α phosphorylation; protein translation; ER stress alleviation; cell survival
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This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. (CC BY 4.0).

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MDPI and ACS Style

Hou, J.-N.; Chen, T.-H.; Chiang, Y.-H.; Peng, J.-Y.; Yang, T.-H.; Cheng, C.-C.; Sofiyatun, E.; Chiu, C.-H.; Chiang-Ni, C.; Chen, W.-J. PERK Signal-Modulated Protein Translation Promotes the Survivability of Dengue 2 Virus-Infected Mosquito Cells and Extends Viral Replication. Viruses 2017, 9, 262.

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