ID | 114915 |
Title Alternative | nsPEFs induce the ISR via ROS-mediated HRI activation
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Author |
Furumoto, Yuji
Tokushima University
Izutani, Akira
Tokushima University
Taniuchi, Shusuke
Tokushima University
Miyake, Masato
Tokushima University
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Teranishi, Kenji
Tokushima University
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Content Type |
Journal Article
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Description | The integrated stress response (ISR) is one of the most important cytoprotective mechanisms and is integrated by phosphorylation of the α subunit of eukaryotic translation initiation factor 2 (eIF2α). Four eIF2α kinases, heme-regulated inhibitor (HRI), double-stranded RNA-dependent protein kinase (PKR), PKR-like endoplasmic reticulum kinase (PERK), and general control nonderepressible 2 (GCN2), are activated in response to several stress conditions. We previously reported that nanosecond pulsed electric fields (nsPEFs) are a potential therapeutic tool for ISR activation. In this study, we examined which eIF2α kinase is activated by nsPEF treatment. To assess the responsible eIF2α kinase, we used previously established eIF2α kinase quadruple knockout (4KO) and single eIF2α kinase-rescued 4KO mouse embryonic fibroblast (MEF) cells. nsPEFs 70 ns in duration with 30 kV/cm electric fields caused eIF2α phosphorylation in wild-type (WT) MEF cells. On the other hand, nsPEF-induced eIF2α phosphorylation was completely abolished in 4KO MEF cells and was recovered by HRI overexpression. CM-H2DCFDA staining showed that nsPEFs generated reactive oxygen species (ROS), which activated HRI. nsPEF-induced eIF2α phosphorylation was blocked by treatment with the ROS scavenger N-acetyl-L-cysteine (NAC). Our results indicate that the eIF2α kinase HRI is responsible for nsPEF-induced ISR activation and is activated by nsPEF-generated ROS.
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Journal Title |
PLOS ONE
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ISSN | 19326203
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Publisher | PLOS
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Volume | 15
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Issue | 3
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Start Page | e0229948
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Published Date | 2020-03-10
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Rights | © 2020 Hamada et al. This is an open access article distributed under the terms of the Creative Commons Attribution License(https://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
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language |
eng
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TextVersion |
Publisher
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departments |
Institute of Advanced Medical Sciences
Science and Technology
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