Skip to main content
bioRxiv
  • Home
  • About
  • Submit
  • ALERTS / RSS
Advanced Search
New Results

Eukaryotic translation initiation factor 2A protects pancreatic beta cells during endoplasmic reticulum stress while rescuing translation inhibition

Evgeniy Panzhinskiy, Søs Skovsø, Haoning Howard Cen, Kwan Yi Chu, Kate MacDonald, Galina Soukhatcheva, Derek A. Dionne, Luisa K. Hallmaier-Wacker, Jennifer S. Wildi, Stephanie Marcil, Nilou Noursadeghi, Farnaz Taghizadeh, C. Bruce Verchere, Eric Jan, View ORCID ProfileJames D. Johnson
doi: https://doi.org/10.1101/2021.02.17.431676
Evgeniy Panzhinskiy
1Diabetes Research Group, Life Sciences Institute, Department of Cellular and Physiological Sciences & Department of Surgery, University of British Columbia, Vancouver, Canada, V6T 1Z3
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • For correspondence: james.d.johnson@ubc.ca epanzhin@mail.ubc.ca ej@mail.ubc.ca
Søs Skovsø
1Diabetes Research Group, Life Sciences Institute, Department of Cellular and Physiological Sciences & Department of Surgery, University of British Columbia, Vancouver, Canada, V6T 1Z3
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Haoning Howard Cen
1Diabetes Research Group, Life Sciences Institute, Department of Cellular and Physiological Sciences & Department of Surgery, University of British Columbia, Vancouver, Canada, V6T 1Z3
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Kwan Yi Chu
1Diabetes Research Group, Life Sciences Institute, Department of Cellular and Physiological Sciences & Department of Surgery, University of British Columbia, Vancouver, Canada, V6T 1Z3
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Kate MacDonald
1Diabetes Research Group, Life Sciences Institute, Department of Cellular and Physiological Sciences & Department of Surgery, University of British Columbia, Vancouver, Canada, V6T 1Z3
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Galina Soukhatcheva
2BC Children’s Hospital Research Institute, Department of Surgery, University of British Columbia, Vancouver, Canada, V5Z 4H4
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Derek A. Dionne
1Diabetes Research Group, Life Sciences Institute, Department of Cellular and Physiological Sciences & Department of Surgery, University of British Columbia, Vancouver, Canada, V6T 1Z3
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Luisa K. Hallmaier-Wacker
1Diabetes Research Group, Life Sciences Institute, Department of Cellular and Physiological Sciences & Department of Surgery, University of British Columbia, Vancouver, Canada, V6T 1Z3
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Jennifer S. Wildi
1Diabetes Research Group, Life Sciences Institute, Department of Cellular and Physiological Sciences & Department of Surgery, University of British Columbia, Vancouver, Canada, V6T 1Z3
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Stephanie Marcil
1Diabetes Research Group, Life Sciences Institute, Department of Cellular and Physiological Sciences & Department of Surgery, University of British Columbia, Vancouver, Canada, V6T 1Z3
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Nilou Noursadeghi
1Diabetes Research Group, Life Sciences Institute, Department of Cellular and Physiological Sciences & Department of Surgery, University of British Columbia, Vancouver, Canada, V6T 1Z3
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Farnaz Taghizadeh
1Diabetes Research Group, Life Sciences Institute, Department of Cellular and Physiological Sciences & Department of Surgery, University of British Columbia, Vancouver, Canada, V6T 1Z3
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
C. Bruce Verchere
2BC Children’s Hospital Research Institute, Department of Surgery, University of British Columbia, Vancouver, Canada, V5Z 4H4
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Eric Jan
3Life Sciences Institute, Department of Biochemistry, University of British Columbia, Vancouver, Canada, V6T 1Z3
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • For correspondence: james.d.johnson@ubc.ca epanzhin@mail.ubc.ca ej@mail.ubc.ca
James D. Johnson
1Diabetes Research Group, Life Sciences Institute, Department of Cellular and Physiological Sciences & Department of Surgery, University of British Columbia, Vancouver, Canada, V6T 1Z3
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • ORCID record for James D. Johnson
  • For correspondence: james.d.johnson@ubc.ca epanzhin@mail.ubc.ca ej@mail.ubc.ca
  • Abstract
  • Full Text
  • Info/History
  • Metrics
  • Data/Code
  • Preview PDF
Loading

ABSTRACT

The endoplasmic reticulum (ER) stress-induced unfolded protein response (UPR) helps decide β cell survival in diabetes. The alternative eukaryotic initiation factor 2A (EIF2A) has been proposed to mediate EIF2S1-independent translation during cellular stress and viral infection, but its role in β cells is unknown. EIF2A abundance is high in human and mouse islets relative to other tissues, and both thapsigargin and palmitate significantly increased EIF2A mRNA and EIF2A protein levels in MIN6 cells, mouse islets and human islets. Knockdowns of EIF2A, the related factor EIF2D, or both EIF2A and EIF2D, were not sufficient to cause apoptosis. On the other hand, transient or stable EIF2A over-expression protected MIN6 cells, primary mouse islets, and human islets from ER stress-induced, caspase-3-dependent apoptosis. Mechanistically, EIF2A overexpression decreased ERN1 (also known as IRE1α) expression in thapsigargin-treated MIN6 cells or human islets. In vivo, β cell specific EIF2A viral overexpression reduced ER stress, improved insulin secretion, and abrogated hyperglycemia in Ins2Akita/WT mice. EIF2A overexpression significantly increased expression of genes involved in protein translation and reduced expression of pro-apoptotic genes (e.g. ALDH1A3). Remarkably, the decrease in global protein synthesis during UPR was prevented by EIF2A, despite ER stress-induced EIF2S1 phosphorylation. The protective effects of EIF2A were additive to those of ISRIB, a drug that counteracts the effects of EIF2S1 phosphorylation. Cells overexpressing EIF2A showed higher expression of translation factor EIF2B5, which may contribute to the lack of translational inhibition in these cells. We conclude that EIF2A is a novel target for β cell protection and the circumvention of EIF2S1-mediated translational repression.

Competing Interest Statement

The authors have declared no competing interest.

Footnotes

  • FUNDING: This work was supported by a Diabetes Investigator Award from Diabetes Canada to JDJ, CIHR grants to EJ (PJT-148761) and CBV (PJT-153156). EP was supported by postdoctoral fellowships from JDRF and UBC.

  • https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE166829

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.
Back to top
PreviousNext
Posted February 17, 2021.
Download PDF
Data/Code
Email

Thank you for your interest in spreading the word about bioRxiv.

NOTE: Your email address is requested solely to identify you as the sender of this article.

Enter multiple addresses on separate lines or separate them with commas.
Eukaryotic translation initiation factor 2A protects pancreatic beta cells during endoplasmic reticulum stress while rescuing translation inhibition
(Your Name) has forwarded a page to you from bioRxiv
(Your Name) thought you would like to see this page from the bioRxiv website.
CAPTCHA
This question is for testing whether or not you are a human visitor and to prevent automated spam submissions.
Share
Eukaryotic translation initiation factor 2A protects pancreatic beta cells during endoplasmic reticulum stress while rescuing translation inhibition
Evgeniy Panzhinskiy, Søs Skovsø, Haoning Howard Cen, Kwan Yi Chu, Kate MacDonald, Galina Soukhatcheva, Derek A. Dionne, Luisa K. Hallmaier-Wacker, Jennifer S. Wildi, Stephanie Marcil, Nilou Noursadeghi, Farnaz Taghizadeh, C. Bruce Verchere, Eric Jan, James D. Johnson
bioRxiv 2021.02.17.431676; doi: https://doi.org/10.1101/2021.02.17.431676
Digg logo Reddit logo Twitter logo Facebook logo Google logo LinkedIn logo Mendeley logo
Citation Tools
Eukaryotic translation initiation factor 2A protects pancreatic beta cells during endoplasmic reticulum stress while rescuing translation inhibition
Evgeniy Panzhinskiy, Søs Skovsø, Haoning Howard Cen, Kwan Yi Chu, Kate MacDonald, Galina Soukhatcheva, Derek A. Dionne, Luisa K. Hallmaier-Wacker, Jennifer S. Wildi, Stephanie Marcil, Nilou Noursadeghi, Farnaz Taghizadeh, C. Bruce Verchere, Eric Jan, James D. Johnson
bioRxiv 2021.02.17.431676; doi: https://doi.org/10.1101/2021.02.17.431676

Citation Manager Formats

  • BibTeX
  • Bookends
  • EasyBib
  • EndNote (tagged)
  • EndNote 8 (xml)
  • Medlars
  • Mendeley
  • Papers
  • RefWorks Tagged
  • Ref Manager
  • RIS
  • Zotero
  • Tweet Widget
  • Facebook Like
  • Google Plus One

Subject Area

  • Physiology
Subject Areas
All Articles
  • Animal Behavior and Cognition (3483)
  • Biochemistry (7336)
  • Bioengineering (5305)
  • Bioinformatics (20219)
  • Biophysics (9990)
  • Cancer Biology (7713)
  • Cell Biology (11280)
  • Clinical Trials (138)
  • Developmental Biology (6426)
  • Ecology (9928)
  • Epidemiology (2065)
  • Evolutionary Biology (13294)
  • Genetics (9353)
  • Genomics (12565)
  • Immunology (7686)
  • Microbiology (18979)
  • Molecular Biology (7427)
  • Neuroscience (40938)
  • Paleontology (300)
  • Pathology (1226)
  • Pharmacology and Toxicology (2132)
  • Physiology (3145)
  • Plant Biology (6850)
  • Scientific Communication and Education (1272)
  • Synthetic Biology (1893)
  • Systems Biology (5306)
  • Zoology (1086)