Eukaryotic Translation Initiation Factor 2A Protects Pancreatic 1 Beta Cells During Endoplasmic Reticulum Stress While Rescuing Translation Inhibition

Panzhinskiy, Evgeniy; Skovsø, Søs; Cen, Haoning Howard; Chu, Kwan Yi; MacDonald, Kate; Soukhatcheva, Galina; Dionne, Derek A.; Hallmaier‐Wacker, Luisa K.; Wildi, Jennifer S.; Marcil, Stephanie; Noursadeghi, Nilou; Taghizadeh, Farnaz; Verchere, C. Bruce; Jan, Eric; Johnson, J.L.

doi:10.2139/ssrn.3866838

Cited by 3 publications

(3 citation statements)

References 54 publications

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“…Uncharacteristic of a translation initiation factor, several studies have provided evidence that eIF2A is non‐cytosolic (Kim et al, 2011; Panzhinskiy et al, 2021; Thul et al, 2017; Uhlen et al, 2010); however, no two reports are in agreement. Unfortunately, eIF2A is not included in the Yeast GFP Fusion Localization Database (Huh et al, 2003).…”

Section: Eif2amentioning

confidence: 99%

“…Whether eIF2A shuttling occurs in other cell types and the mechanism was not reported. Enigmatically, eIF2A has been reported to also co‐localize with the ER in MIN6 cells (Panzhinskiy et al, 2021) and have localization pattern resembling mitochondria in U2OS and A‐431 cells. It is not clear how eIF2A could function in translation initiation if localized or sequestered away from the translation machinery in the cytosol.…”

Section: Critical Questions Moving Forwardmentioning

confidence: 99%

“…To our knowledge, whether this localization pattern is due to an alternate function of eIF2A, such as ribosome assembly, is not reported. Second, Panzhinskiy et al demonstrated that eIF2A co‐localizes with the endoplasmic reticulum (ER) in MIN6 cells during normal physiological conditions (Panzhinskiy et al, 2021). ER localization during normal conditions is uncharacteristic of a translation initiation factor since translation initiation occurs in the cytosol.…”

Section: Eif2amentioning

confidence: 99%

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To initiate or not to initiate: A critical assessment of eIF2A, eIF2D, and MCT‐1·DENR to deliver initiator tRNA to ribosomes

Grove,

Russell,

Kearse

2024

WIREs RNA

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Selection of the correct start codon is critical for high‐fidelity protein synthesis. In eukaryotes, this is typically governed by a multitude of initiation factors (eIFs), including eIF2·GTP that directly delivers the initiator tRNA (Met‐tRNAiMet) to the P site of the ribosome. However, numerous reports, some dating back to the early 1970s, have described other initiation factors having high affinity for the initiator tRNA and the ability of delivering it to the ribosome, which has provided a foundation for further work demonstrating non‐canonical initiation mechanisms using alternative initiation factors. Here we provide a critical analysis of current understanding of eIF2A, eIF2D, and the MCT‐1·DENR dimer, the evidence surrounding their ability to initiate translation, their implications in human disease, and lay out important key questions for the field.This article is categorized under: RNA Interactions with Proteins and Other Molecules > RNA‐Protein Complexes Translation > Mechanisms Translation > Regulation

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Section: Eif2amentioning

confidence: 99%

Section: Critical Questions Moving Forwardmentioning

confidence: 99%

Section: Eif2amentioning

confidence: 99%

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To initiate or not to initiate: A critical assessment of eIF2A, eIF2D, and MCT‐1·DENR to deliver initiator tRNA to ribosomes

Grove,

Russell,

Kearse

2024

WIREs RNA

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Increased levels of eIF2A inhibit translation by sequestering 40S ribosomal subunits

Grove,

Levine,

Kearse

2023

Nucleic Acids Research

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eIF2A was the first eukaryotic initiator tRNA carrier discovered but its exact function has remained enigmatic. Uncharacteristic of translation initiation factors, eIF2A is reported to be non-cytosolic in multiple human cancer cell lines. Attempts to study eIF2A mechanistically have been limited by the inability to achieve high yield of soluble recombinant protein. Here, we developed a purification paradigm that yields ∼360-fold and ∼6000-fold more recombinant human eIF2A from Escherichia coli and insect cells, respectively, than previous reports. Using a mammalian in vitro translation system, we found that increased levels of recombinant human eIF2A inhibit translation of multiple reporter mRNAs, including those that are translated by cognate and near-cognate start codons, and does so prior to start codon recognition. eIF2A also inhibited translation directed by all four types of cap-independent viral IRESs, including the CrPV IGR IRES that does not require initiation factors or initiator tRNA, suggesting excess eIF2A sequesters 40S subunits. Supplementation with additional 40S subunits prevented eIF2A-mediated inhibition and pull-down assays demonstrated direct binding between recombinant eIF2A and purified 40S subunits. These data support a model that eIF2A must be kept away from the translation machinery to avoid sequestering 40S ribosomal subunits.

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Sex differences in islet stress responses support female beta cell resilience

Brownrigg

Xia

Chu

et al. 2022

Preprint

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Type 2 diabetes risk is ∼40% higher in men than in pre-menopausal women. Despite evidence that sex differences in pancreatic β cells play a role in this differential diabetes risk, few studies have examined diabetes-associated changes to β cell function in each sex. Our single-cell analysis of human β cells revealed profound sex-specific changes to gene expression and function in type 2 diabetes. To gain deeper insight into sex differences in β cells, we generated a well-powered islet RNAseq dataset from 20-week-old male and female mice with equivalent insulin sensitivity. This unbiased analysis revealed differential enrichment of unfolded protein response pathway-associated genes, where female islets showed higher expression of genes linked with protein synthesis, folding, and processing. This differential expression was biologically significant, as female islets were more resilient to endoplasmic reticulum (ER) stress induction with thapsigargin. Specifically, female islets maintained better insulin secretion and showed a distinct transcriptional response under ER stress compared with males. Given the known links between ER stress and T2D pathogenesis, our findings suggest sex differences in β cells contribute to the differential T2D risk between men and women.

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Eukaryotic Translation Initiation Factor 2A Protects Pancreatic 1 Beta Cells During Endoplasmic Reticulum Stress While Rescuing Translation Inhibition

Abstract: We thank members of the Johnson and Jan labs for helpful discussions.

Cited by 3 publications

References 54 publications

To initiate or not to initiate: A critical assessment of eIF2A, eIF2D, and MCT‐1·DENR to deliver initiator tRNA to ribosomes

To initiate or not to initiate: A critical assessment of eIF2A, eIF2D, and MCT‐1·DENR to deliver initiator tRNA to ribosomes

Increased levels of eIF2A inhibit translation by sequestering 40S ribosomal subunits

Sex differences in islet stress responses support female beta cell resilience

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