ArticlePloS one2016
Paradoxical Sensitivity to an Integrated Stress Response Blocking Mutation in Vanishing White Matter Cells.
Article in PloS one, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 19 papers.
What it found
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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
19 citing papers in PubMed, 33 citations in OpenAlex.
- A molecular stabiliser of an inhibitory eIF2B-eIF2(αP) complex activates the Integrated Stress Response.Nature communications · 2026Article
- Regulation of Translation of ATF4 mRNA: A Focus on Translation Initiation Factors and RNA-Binding Proteins.Cells · 2026Review
- Fluorescence Intensity-Based eIF2B's Guanine Nucleotide-Exchange Factor Activity Assay.Methods in molecular biology (Clifton, N.J.) · 2022Article
- Cargo receptor-assisted endoplasmic reticulum export of pathogenic α1-antitrypsin polymers.Cell reports · 2021Article
- ISRIB Blunts the Integrated Stress Response by Allosterically Antagonising the Inhibitory Effect of Phosphorylated eIF2 on eIF2B.Molecular cell · 2021Article
- Vanishing white matter disease expression of truncated EIF2B5 activates induced stress response.eLife · 2020Article
- Calcium depletion challenges endoplasmic reticulum proteostasis by destabilising BiP-substrate complexes.eLife · 2020Article
- Unfolded protein response in myelin disorders.Neural regeneration research · 2020Review
- Article
- An oligomeric state-dependent switch in the ER enzyme FICD regulates AMPylation and deAMPylation of BiP.The EMBO journal · 2019Article
- MANF antagonizes nucleotide exchange by the endoplasmic reticulum chaperone BiP.Nature communications · 2019Article
- Article
- Binding of ISRIB reveals a regulatory site in the nucleotide exchange factor eIF2B.Science (New York, N.Y.) · 2018Article
- Adult mouse eIF2Bε Arg191His astrocytes display a normal integrated stress response in vitro.Scientific reports · 2018Article
- Article
- A J-Protein Co-chaperone Recruits BiP to Monomerize IRE1 and Repress the Unfolded Protein Response.Cell · 2017Article
- Generic membrane-spanning features endow IRE1α with responsiveness to membrane aberrancy.Molecular biology of the cell · 2017Article
- Article
- Endoplasmic Reticulum Protein Quality Control Failure in Myelin Disorders.Frontiers in molecular neuroscience · 2016Review
Corrections and comments
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Authors and funding
6 authors at 1 institution in 1 country.
Funding
Abstract
The eukaryotic translation initiation factor eIF2B promotes mRNA translation as a guanine nucleotide exchange factor (GEF) for translation initiation factor 2 (eIF2). Endoplasmic reticulum (ER) stress-mediated activation of the kinase PERK and the resultant phosphorylation of eIF2's alpha subunit (eIF2α) attenuates eIF2B GEF activity thereby inducing an integrated stress response (ISR) that defends against protein misfolding in the ER. Mutations in all five subunits of human eIF2B cause an inherited leukoencephalopathy with vanishing white matter (VWM), but the role of the ISR in its pathogenesis remains unclear. Using CRISPR-Cas9 genome editing we introduced the most severe known VWM mutation, EIF2B4A391D, into CHO cells. Compared to isogenic wildtype cells, GEF activity of cells with the VWM mutation was impaired and the mutant cells experienced modest enhancement of the ISR. However, despite their enhanced ISR, imposed by the intrinsic defect in eIF2B, disrupting the inhibitory effect of phosphorylated eIF2α on GEF by a contravening EIF2S1/eIF2αS51A mutation that functions upstream of eIF2B, selectively enfeebled both EIF2B4A391D and the related severe VWM EIF2B4R483W cells. The basis for paradoxical dependence of cells with the VWM mutations on an intact eIF2α genotype remains unclear, as both translation rates and survival from stressors that normally activate the ISR were not reproducibly affected by the VWM mutations. Nonetheless, our findings support an additional layer of complexity in the development of VWM, beyond a hyperactive ISR.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.