Nanosecond pulsed electric fields induce the integrated stress response via reactive oxygen species-mediated heme-regulated inhibitor (HRI) activation.

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  • Additional Information
    • Source:
      Publisher: Public Library of Science Country of Publication: United States NLM ID: 101285081 Publication Model: eCollection Cited Medium: Internet ISSN: 1932-6203 (Electronic) Linking ISSN: 19326203 NLM ISO Abbreviation: PLoS One Subsets: MEDLINE
    • Publication Information:
      Original Publication: San Francisco, CA : Public Library of Science
    • Subject Terms:
      Electricity/*adverse effects ; Fibroblasts/*metabolism ; Protein Serine-Threonine Kinases/*metabolism ; Reactive Oxygen Species/*metabolism ; Stress, Physiological/*physiology; Acetylcysteine/pharmacology ; Animals ; Cell Line ; Gene Knockout Techniques ; Mice ; Phosphorylation ; Protein Serine-Threonine Kinases/genetics ; Reactive Oxygen Species/antagonists & inhibitors ; Stress, Physiological/drug effects ; eIF-2 Kinase/genetics
    • Abstract:
      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.
      Competing Interests: The authors have declared that no competing interests exist.
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    • Accession Number:
      0 (Reactive Oxygen Species)
      EC 2.7.11.1 (Eif2ak4 protein, mouse)
      EC 2.7.11.1 (PERK kinase)
      EC 2.7.11.1 (Protein Serine-Threonine Kinases)
      EC 2.7.11.1 (eIF-2 Kinase)
      EC 2.7.11.1 (eIF2alpha kinase, mouse)
      EC 2.7.11.1 (protein kinase R, mouse)
      WYQ7N0BPYC (Acetylcysteine)
    • Publication Date:
      Date Created: 20200311 Date Completed: 20200619 Latest Revision: 20211204
    • Publication Date:
      20240105
    • Accession Number:
      PMC7064201
    • Accession Number:
      10.1371/journal.pone.0229948
    • Accession Number:
      32155190