RT Journal Article
SR Electronic
T1 Eukaryotic translation initiation factor 2A protects pancreatic beta cells during endoplasmic reticulum stress while rescuing translation inhibition
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2021.02.17.431676
DO 10.1101/2021.02.17.431676
A1 Evgeniy Panzhinskiy
A1 Søs Skovsø
A1 Haoning Howard Cen
A1 Kwan Yi Chu
A1 Kate MacDonald
A1 Galina Soukhatcheva
A1 Derek A. Dionne
A1 Luisa K. Hallmaier-Wacker
A1 Jennifer S. Wildi
A1 Stephanie Marcil
A1 Nilou Noursadeghi
A1 Farnaz Taghizadeh
A1 C. Bruce Verchere
A1 Eric Jan
A1 James D. Johnson
YR 2021
UL http://biorxiv.org/content/early/2021/02/17/2021.02.17.431676.abstract
AB 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 StatementThe authors have declared no competing interest.