Affinage

EIF2B5

Translation initiation factor eIF2B subunit epsilon · UniProt Q13144

Length
721 aa
Mass
80.4 kDa
Annotated
2026-04-28
71 papers in source corpus 31 papers cited in narrative 29 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

EIF2B5 encodes the catalytic epsilon subunit of the heteropentameric guanine nucleotide exchange factor eIF2B, which recycles eIF2·GDP to eIF2·GTP to enable formation of the eIF2·GTP·Met-tRNAi ternary complex essential for translation initiation (PMID:7803480, PMID:8168527). The C-terminal domain of eIF2Bε harbors intrinsic GEF activity and binds eIF2, while an N-terminal activation domain amplifies exchange activity upon assembly with the other four eIF2B subunits (PMID:10805739, PMID:23335982). eIF2Bε is negatively regulated by sequential phosphorylation—DYRK1A/2 primes Ser-539, enabling GSK-3β to phosphorylate the inhibitory Ser-535 site—and is further inhibited when stress-kinase-phosphorylated eIF2α sequesters the holoenzyme; insulin/PI3K/AKT signaling relieves GSK-3β-mediated inhibition, while MEK/ERK provides a phosphorylation-independent activation input (PMID:8397507, PMID:11311121, PMID:12133000, PMID:10913625). Biallelic EIF2B5 mutations cause vanishing white matter disease (VWM/CACH), with oligodendrocyte-specific loss of eIF2Bε GEF activity being the primary driver of myelination defects and ataxia, while astrocyte-specific dysfunction contributes to vacuolization and integrated stress response dysregulation (PMID:15723074, PMID:31587290, PMID:40326783).

Mechanistic history

Synthesis pass · year-by-year structured walk · 19 steps
  1. 1987 Medium

    Establishing that eIF-2B is the critical factor that reverses phospho-eIF2α-mediated translational inhibition by recycling eIF-2·GDP on ribosomes answered the question of how translational repression by eIF-2α kinases is mechanistically implemented.

    Evidence Rabbit reticulocyte lysate polysome fractionation with exogenous eIF-2B addition

    PMID:3646234

    Open questions at the time
    • Single reconstitution system (reticulocyte lysate); subunit composition of active eIF-2B not determined
    • Mechanism of phospho-eIF2α-mediated sequestration not resolved
  2. 1992 High

    Demonstrating that ER stress agents increase eIF-2α phosphorylation and reduce eIF-2B activity in intact cells established the first link between organellar stress and eIF-2B-dependent translational control.

    Evidence GH3 cell ER stress (thapsigargin/DTT); isoelectric focusing of eIF-2α; eIF-2B activity assays

    PMID:1512215

    Open questions at the time
    • Identity of the ER stress kinase (later identified as PERK) unknown at this time
    • Whether eIF-2B subunit composition changes under stress not tested
  3. 1993 High

    Identifying GSK-3 as the kinase that phosphorylates eIF2Bε and showing insulin inactivates GSK-3 revealed a direct signaling axis from growth factors to translational control via eIF2B.

    Evidence Chromatographic fractionation of CHO cell extracts; kinase assays; GSK-3 isoform-specific immunoblotting

    PMID:8397507

    Open questions at the time
    • Exact phosphorylation site on eIF2Bε not yet identified
    • Whether GSK-3 requires a priming kinase not yet known
  4. 1994 High

    Biochemical purification confirmed eIF-2B as a heteropentamer whose ε subunit is the catalytic component, while genetic epistasis in yeast showed phospho-eIF2α acts as a competitive inhibitor (not an irreversible poison) and that the β/δ subunits mediate the regulatory response to phospho-eIF2α.

    Evidence Purification from rat/bovine liver with GEF assays; yeast overexpression/suppressor genetics with GCN4-lacZ reporters; CHO cell eIF-2α mutagenesis with HRI kinase

    PMID:7565788 PMID:7803480 PMID:8007958 PMID:8164676 PMID:8168527

    Open questions at the time
    • No structural information on the pentamer
    • How ε cooperates with the regulatory subcomplexes not resolved at the protein level
  5. 1996 High

    Glucose-stimulated eIF-2B activation in pancreatic islets independent of eIF-2α phosphorylation demonstrated that eIF2B activity is regulated by nutrient signals through mechanisms beyond the canonical phospho-eIF2α pathway.

    Evidence Isolated rat pancreatic islets; GEF assays; isoelectric focusing of eIF-2α

    PMID:8567668

    Open questions at the time
    • Molecular target on eIF2B for glucose signal unknown
    • Whether eIF2Bε phosphorylation changes were not tested
  6. 2000 High

    Systematic mutagenesis of yeast eIF2Bε mapped catalytic GEF activity and eIF2 binding to the C-terminal domain and identified a distinct N-terminal activation domain responsive to holoenzyme assembly, establishing a two-domain architecture for eIF2Bε function.

    Evidence Yeast GCD6 mutagenesis (nonsense, missense, deletions); in vitro GEF assays; co-immunoprecipitation

    PMID:10805739

    Open questions at the time
    • No atomic-resolution structure of either domain
    • How N-terminal domain senses assembly not mechanistically resolved
  7. 2000 Medium

    EGF/NGF activation of eIF-2B via MEK/ERK without changes in Ser-535 phosphorylation revealed a phosphorylation-independent regulatory input, indicating multiple convergent pathways control eIF2Bε.

    Evidence PC12 cell pharmacological inhibition (PD98059); eIF-2B activity assays; phospho-Ser535 immunoblotting

    PMID:10913625

    Open questions at the time
    • Target of MEK/ERK on eIF2B not identified
    • Single cell type and single lab
    • Whether a distinct phosphorylation site is involved not excluded
  8. 2001 High

    Identification of DYRK1A/2 as the priming kinases for Ser-539 that enables GSK-3β to phosphorylate Ser-535 completed the sequential phosphorylation mechanism governing eIF2Bε inhibition.

    Evidence In vitro kinase assays with purified DYRKs, GSK-3, eIF2Bε peptides; mass spectrometry; in vivo phosphorylation analysis

    PMID:11311121

    Open questions at the time
    • Whether DYRK phosphorylation is itself regulated by signaling pathways not determined
    • Phosphatase(s) that dephosphorylate these sites not identified
  9. 2002 High

    Pharmacological GSK-3 inhibition confirmed in vivo Ser-535 phosphorylation but showed it was insufficient for insulin-mediated eIF2B activation, proving that additional regulatory inputs exist beyond the GSK-3-Ser535 axis.

    Evidence CHO cells treated with GSK-3 inhibitors (LiCl, SB-415286, SB-216763); phospho-specific antibodies; eIF2B activity assays

    PMID:12133000

    Open questions at the time
    • Identity of the additional regulatory input(s) unknown
    • Whether they converge on eIF2Bε or other subunits not resolved
  10. 2002 High

    The first in vivo demonstration that sepsis increases eIF2Bε-Ser535 phosphorylation via TNF-mediated GSK-3 activation in skeletal muscle established pathological relevance of eIF2Bε phosphoregulation.

    Evidence Rat sepsis model; phospho-specific antibodies; eIF2B activity assays; TNF-binding protein rescue

    PMID:12376332

    Open questions at the time
    • Whether TNF acts directly on muscle GSK-3 or via intermediary signaling not resolved
    • Contribution of eIF-2α phosphorylation in sepsis not fully dissected
  11. 2005 High

    Demonstrating that VWM patient-derived cells and EIF2B5-knockdown normal progenitors both fail to generate GFAP+ astrocytes established a cell-autonomous role for eIF2Bε in glial differentiation and connected EIF2B5 mutations to VWM disease pathology.

    Evidence Primary cultures from VWM patient brain; GFAP immunostaining; siRNA knockdown of EIF2B5 in normal human glial progenitors

    PMID:15723074

    Open questions at the time
    • Molecular mechanism linking reduced GEF activity to astrocyte differentiation not identified
    • Oligodendrocyte contribution not examined in this study
  12. 2010 High

    Ectopic expression of eIF2Bε in rat skeletal muscle rescued sepsis-induced eIF2B GEF deficits and protein synthesis, showing that eIF2Bε expression level is rate-limiting for translation in catabolic states.

    Evidence In vivo plasmid transfection into rat tibialis anterior; sepsis model; GEF assays; metabolic labeling

    PMID:20484009

    Open questions at the time
    • Whether eIF2Bε stoichiometry with other subunits is maintained during overexpression not determined
    • Long-term therapeutic potential not assessed
  13. 2012 Medium

    Mapping the pyrophosphorylase-like and left-handed β-helix domains as mediating eIF2Bε–eIF2Bγ inter-subunit contacts clarified the structural basis for holoenzyme assembly, distinct from the C-terminal catalytic domain.

    Evidence Yeast genetic analysis; co-expression/co-precipitation of domain constructs

    PMID:22238343

    Open questions at the time
    • No high-resolution structure available at this time
    • Whether these domains contribute to regulation not tested
    • Single lab study
  14. 2013 High

    Purified human eIF2Bε C-terminal domain demonstrated GEF activity that was reduced by VWM mutations, directly linking patient genotypes to catalytic impairment; concurrently, DYRK2 was shown to regulate cardiomyocyte size through the DYRK2→GSK-3β→eIF2Bε-Ser535 axis, extending eIF2Bε phosphoregulation to cardiac hypertrophy.

    Evidence Recombinant human eIF2Bε catalytic domain purified from yeast with in vitro GEF assays; transgenic mice with eIF2Bε-S535A; adenoviral DYRK2 overexpression/knockdown in cardiomyocytes

    PMID:23335982 PMID:24023715

    Open questions at the time
    • Full holoenzyme reconstitution with VWM mutant subunits not achieved
    • Whether cardiac hypertrophy phenotype involves ISR activation not tested
  15. 2016 High

    Constitutively active eIF2Bε promoted CNS axon regeneration downstream of AKT-GSK-3β and independently of mTORC1, revealing a new biological role for eIF2B-dependent translation in neural repair.

    Evidence Mouse optic nerve injury model; conditional Pten deletion with constitutively active or dominant-negative eIF2Bε constructs; axon counting

    PMID:26974342

    Open questions at the time
    • Which mRNAs are translationally upregulated by eIF2Bε in regenerating axons not identified
    • Whether endogenous eIF2Bε is rate-limiting in the regeneration context not tested
  16. 2017 High

    Hypoxia-induced intron retention in EIF2B5 produces a dominant-negative truncated isoform that inhibits global translation, revealing a post-transcriptional layer of eIF2Bε regulation involving SRSF3-mediated cotranscriptional splicing.

    Evidence RNA-seq; minigene splicing assays; polysome profiling; RIP for SRSF3; ChIP for phospho-Pol II in cancer cells

    PMID:28961236

    Open questions at the time
    • In vivo physiological relevance of intron retention beyond cancer cell lines not established
    • Whether this mechanism operates in normal tissue hypoxia (e.g., embryonic development) unknown
  17. 2019 High

    A spontaneous Eif2b5 point mutation in mice directly linked reduced GEF activity to white matter disruption, ATF4 elevation, epileptic seizures, and oligodendrocyte progenitor clustering, providing the first single-gene mouse model recapitulating VWM-like neuropathology.

    Evidence Spontaneous mouse mutant; biochemical GEF assay; immunohistochemistry; behavioral testing

    PMID:31587290

    Open questions at the time
    • Whether ATF4 elevation is cause or consequence of pathology not resolved
    • Mechanism of oligodendrocyte progenitor clustering unknown
  18. 2021 Medium

    eIF2Bε GEF activity was shown to be required for Wnt-mediated intestinal stem cell clonogenicity and Paneth cell maturation, broadening eIF2Bε function beyond the CNS to epithelial homeostasis.

    Evidence eIF2Bε-R191H knock-in mice; intestinal organoid culture; Wnt activation by GSK3β inhibitor; stemness markers

    PMID:34399164

    Open questions at the time
    • Whether the phenotype is specific to eIF2Bε or general to eIF2B holoenzyme insufficiency not distinguished
    • Translational targets downstream of Wnt-eIF2B axis not identified
    • Single lab study
  19. 2025 High

    Cell-type-specific conditional Eif2b5 mutagenesis resolved a longstanding question by showing that oligodendrocyte-intrinsic eIF2Bε dysfunction is the primary driver of VWM motor phenotype and myelination defects, while astrocyte-intrinsic dysfunction drives vacuolization and ISR activation.

    Evidence Three conditional Eif2b5 mouse lines (oligodendrocyte, astrocyte, neuron Cre); motor behavior; neuropathology; ISR gene expression

    PMID:40326783

    Open questions at the time
    • Molecular mechanism by which reduced GEF activity specifically impairs oligodendrocyte maturation unknown
    • Whether therapeutic GEF restoration in specific cell types is sufficient for rescue not tested

Open questions

Synthesis pass · forward-looking unresolved questions
  • Major open questions include: which specific mRNAs are translationally controlled by eIF2Bε activity changes in disease-relevant cell types; what phosphatases reverse Ser-535/Ser-539 phosphorylation; and what the complete structural basis is for VWM mutation-induced GEF impairment in the human holoenzyme context.
  • No translatome profiling of eIF2Bε-mutant cells in disease-relevant lineages
  • Phosphatase(s) acting on eIF2Bε not identified
  • Full structural impact of VWM mutations in assembled human decamer not resolved

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0098772 molecular function regulator activity 5
Localization
GO:0005829 cytosol 2
Pathway
R-HSA-392499 Metabolism of proteins 6 R-HSA-162582 Signal Transduction 4 R-HSA-8953897 Cellular responses to stimuli 3 R-HSA-8953854 Metabolism of RNA 1
Partners
DYRK1ADYRK2EIF2B1EIF2B2EIF2B3EIF2B4EIF2S1GSK3B
Complex memberships
eIF2B

Evidence

Reading pass · 29 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1993 Glycogen synthase kinase-3 (GSK-3) phosphorylates the epsilon subunit of eIF-2B, and insulin rapidly inactivates GSK-3 (via phosphorylation of GSK-3 itself, reversible by protein phosphatase-2A), thereby modulating eIF-2B activity. Chromatographic fractionation of CHO cell extracts, kinase assays with GSK-3-specific peptide substrates, immunoblotting with isoform-specific GSK-3 antibodies, phosphatase treatment The Biochemical journal High 8397507
1994 eIF-2B is the guanine nucleotide exchange factor (GEF) for eIF-2; it promotes release of GDP from inactive eIF-2·GDP complexes to allow formation of active eIF-2·GTP, and this activity is inhibited when the alpha subunit of eIF-2 is phosphorylated. eIF-2B is a heteropentamer (subunits α, β, γ, δ, ε); the ε subunit is the catalytic subunit phosphorylated by protein kinases in liver extracts. Purification of eIF-2B from rat/bovine liver to >95% homogeneity; guanine nucleotide exchange assays; monoclonal antibody generation; protein kinase assays on individual subunits Biochimica et biophysica acta / Biochimie / European journal of biochemistry High 7803480 7893825 8168527
1994 Phosphorylation of eIF-2α at Ser-51 by eIF-2α kinase (HRI) inhibits eIF-2B guanine nucleotide exchange activity in cell extracts; Ser-48 of eIF-2α also contributes by maintaining high-affinity interaction between phosphorylated eIF-2α and eIF-2B, sequestering eIF-2B in an inactive complex. Cell extracts from CHO cells overexpressing wild-type or mutant eIF-2α (S48A, S51A); in vitro kinase treatment with purified HRI; GEF activity assays Molecular and cellular biology High 8007958
1994 Overexpression of all five subunits of eIF-2B suppresses the growth-inhibitory and translational effects of eIF-2α hyperphosphorylation in yeast, establishing that phosphorylated eIF-2 acts as a competitive inhibitor of eIF-2B (rather than forming an irreversible inhibitory complex), and that eIF-2·GTP·Met-tRNA ternary complex concentration is the cardinal parameter controlling translation. Yeast genetic overexpression of eIF-2B subunits (all five), gene dosage experiments, GCN4-lacZ reporter assays, genetic epistasis Molecular and cellular biology High 7565788
1994 Mutations in the GCD7 (β) and GCD2 (δ) subunits of yeast eIF-2B suppress inhibition by phosphorylated eIF-2α, revealing that these subunits mediate the regulatory interaction between phospho-eIF-2 and eIF-2B without impairing the essential catalytic function, and that the eIF-2B complex can be rendered insensitive to eIF-2α phosphorylation. Yeast suppressor screen; GCN4-lacZ reporter; in vivo phosphorylation assays; growth assays with activated GCN2c kinase Molecular and cellular biology High 8164676
2000 The C-terminal domain of eIF2Bε (residues 518–712 in yeast) is required for both catalytic GEF activity and binding to eIF-2; the N-terminal half of eIF2Bε contains an activation domain that responds to complex formation with other eIF2B subunits to enhance the nucleotide exchange rate, but missense mutations in this domain impair complex-stimulated activity without affecting intrinsic exchange activity or eIF2 binding. Yeast mutagenesis (nonsense, missense, in-frame deletions) of GCD6 (eIF2Bε); in vitro GEF assays with purified proteins; co-immunoprecipitation of subunit interactions Molecular and cellular biology High 10805739
2001 DYRK2 and DYRK1A phosphorylate Ser-539 (rat numbering) in eIF2Bε, which is a priming phosphorylation that enables GSK-3 to subsequently phosphorylate the inhibitory Ser-535 site; eIF2Bε is highly phosphorylated at Ser-539 in vivo. In vitro kinase assays with purified DYRK isoforms, GSK-3, and eIF2Bε peptides/protein; mass spectrometry of phosphorylation sites; in vivo phosphorylation analysis The Biochemical journal High 11311121
2002 GSK-3 phosphorylates Ser-535 of eIF2Bε in vivo (confirmed by GSK-3 inhibitors LiCl, SB-415286, SB-216763 causing dephosphorylation), but dephosphorylation of Ser-535 alone is insufficient to activate eIF-2B in response to insulin, indicating that additional regulatory inputs are required for eIF2B activation. Pharmacological GSK-3 inhibitors in CHO cells; phospho-specific antibodies against Ser-535; eIF2B activity assays; phosphoinositide 3-kinase pathway inhibitors The Biochemical journal High 12133000
1992 Agents that disrupt ER Ca2+ homeostasis (thapsigargin, A23187, EGTA, DTT) inhibit translational initiation in GH3 cells concomitantly with ~5-fold increase in eIF-2α phosphorylation and ~50% reduction in eIF-2B activity, establishing that ER stress leads to eIF-2B inhibition via eIF-2α phosphorylation. Metabolic labeling, isoelectric focusing of eIF-2α, eIF-2B activity assays, acute and chronic drug treatment in intact cells The Journal of biological chemistry High 1512215
1996 Glucose activates eIF-2B activity in isolated rat pancreatic islets within 15 min via a pathway independent of changes in eIF-2α phosphorylation, indicating a direct regulatory mechanism for eIF-2B activity by glucose metabolism. Isolated rat islet preparations; guanine nucleotide exchange assays; isoelectric focusing of eIF-2α; non-metabolizable glucose analogue controls The Journal of biological chemistry High 8567668
2002 Sepsis increases GSK-3 activity (reduced Ser-9 phosphorylation of GSK-3β) and augments phosphorylation of eIF2Bε-Ser-535 by >2-fold in rat skeletal muscle, reducing eIF2B activity; TNF-binding protein treatment prevented these changes, implicating TNF as the mediator. This provides the first in vivo demonstration of eIF2Bε phosphorylation changes. Rat sepsis model; phospho-specific antibodies; eIF2B kinase/phosphatase activity assays; in vivo pharmacological intervention with TNF-binding protein American journal of physiology. Endocrinology and metabolism High 12376332
2000 EGF- and NGF-induced activation of eIF-2B in PC12 cells requires MEK/ERK signaling (blocked by PD98059), and this activation is accompanied by GSK-3 inactivation; however, activation of eIF-2B occurs without detectable change in Ser-535 phosphorylation of eIF2Bε, indicating MEK/ERK-dependent but GSK-3/Ser-535-independent regulatory mechanisms. PC12 cell pharmacological inhibition (PD98059); eIF-2B activity assays; phospho-specific antibody detection of Ser-535 FEBS letters Medium 10913625
2008 Resistance exercise in young men reduces phosphorylation of eIF2Bε at Ser-540 (equivalent to rat Ser-535) in skeletal muscle, consistent with GSK-3 inhibition and eIF-2B activation, linking exercise signaling to eIF2Bε dephosphorylation. Human skeletal muscle biopsies; phospho-specific immunoblotting; unilateral exercise design with contralateral control American journal of physiology. Regulatory, integrative and comparative physiology Medium 18565837
2005 EIF2B5 mutations in VWM patient cells severely compromise the generation of GFAP+ astrocytes from glial progenitors; RNAi targeting of EIF2B5 in normal human glial progenitors phenocopies this defect, establishing a specific cell-autonomous role for eIF2Bε in astrocyte differentiation. Primary cell culture from VWM patient brain; GFAP immunostaining; siRNA knockdown of EIF2B5 in normal human glial progenitors Nature medicine High 15723074
2013 DYRK2 negatively regulates cardiomyocyte growth by priming GSK-3β-mediated phosphorylation and inhibition of eIF2Bε; DYRK2 overexpression increases p-Ser535-eIF2Bε and reduces cardiomyocyte size, while DYRK2 knockdown decreases p-Ser535-eIF2Bε; constitutively active eIF2Bε-S535A causes cardiac hypertrophy in transgenic mice. Transgenic mice overexpressing eIF2Bε or eIF2Bε-S535A; adenoviral overexpression of DYRK2 in cardiomyocytes; siRNA knockdown of DYRK2; phospho-specific immunoblotting; cardiac morphometry PloS one High 24023715
2012 The pyrophosphorylase-like domain (PLD) and left-handed β-helix domain of eIF2Bε and eIF2Bγ mediate critical inter-subunit interactions required for eIF2B complex formation; no evidence supports the PLD of eIF2Bε contributing to nucleotide exchange activity directly. Yeast genetic analysis; co-expression and co-precipitation of deletion/domain constructs; predicted structural modeling The Journal of biological chemistry Medium 22238343
2013 The C-terminal domain of human eIF2Bε has GEF activity when expressed and purified from yeast; VWM disease mutations within this domain reduce its GEF activity, confirming that the catalytic domain of eIF2Bε is directly impaired by VWM mutations. Affinity purification of recombinant human eIF2Bε C-terminal domain from engineered yeast; in vitro GEF assays; comparison with patient lymphocyte-derived eIF2B activity PloS one High 23335982
2016 eIF2Bε acts as a downstream effector of the AKT-GSK-3β signaling axis in CNS axon regeneration; inactivation of eIF2Bε reduces GSK-3β and AKT-mediated axon regeneration of retinal ganglion cells after optic nerve injury, while constitutively active eIF2Bε is sufficient to promote axon regeneration independently of mTORC1. Mouse optic nerve injury model; conditional Pten deletion; genetic epistasis with constitutively active and dominant-negative eIF2Bε constructs; retinal ganglion cell survival and axon counting eLife High 26974342
2017 Under hypoxia, intron retention in EIF2B5 generates a 65 kDa truncated eIF2Bε isoform that acts as a dominant-negative to inhibit global translation; this is mediated by hypoxia-induced SRSF3 binding at the retained intron and increased Ser2-phosphorylated RNA Pol II at this region during cotranscriptional processing. RNA-seq/exon-level analysis; minigene splicing assays; expression of truncated isoform in cancer cells; polysome profiling; RIP assays for SRSF3; ChIP for phospho-Pol II PLoS biology High 28961236
2010 Ectopic expression of eIF2Bε in rat skeletal muscle increases GEF activity in healthy animals and rescues the sepsis-induced deficit in eIF2B GEF activity and muscle protein synthesis, demonstrating that eIF2Bε expression level is rate-limiting and sufficient to correct eIF2B deficits. In vivo plasmid transfection into tibialis anterior; sepsis rat model; GEF activity assays; protein synthesis measurement by metabolic labeling American journal of physiology. Endocrinology and metabolism High 20484009
2019 A point mutation in mouse Eif2b5 (p.Ile98Met) decreases eIF2B guanine nucleotide exchange activity on eIF2, elevates ATF4 (ER stress marker) in brain, causes white matter disruption with oligodendrocyte progenitor clustering, and produces neurological phenotypes including epileptic seizures and infertility, establishing direct links between eIF2Bε GEF function and CNS homeostasis. Spontaneous mutant mouse characterization; biochemical GEF assay; immunohistochemistry; GFAP and CHOP mRNA expression; behavioral testing Journal of neurochemistry High 31587290
2020 In zebrafish VWM models, intron 12 retention in eif2b5 leads to a truncated eif2b5 transcript; expression of this truncated eif2b5 in wild-type larvae activates the integrated stress response (ISR) and impairs motor behavior, suggesting a feed-forward gain-of-function mechanism contributing to VWM pathophysiology. Zebrafish eif2b5 mutant generation; RNA analysis; rescue by human EIF2B2 expression; motor behavioral assays; ISR marker analysis eLife Medium 33300869
2021 eIF2Bε promotes Wnt-mediated clonogenicity and global translational capacity in intestinal epithelial cells; eIF2BεArg191His (reduced GEF activity) mice show impaired crypt formation, reduced stemness marker expression, and defective Paneth cell granule formation; eIF2Bε is essential for Wnt hyperactivation-associated translational increase in organoids. eIF2Bε Arg191His knock-in mice; intestinal organoid culture; GSK3β inhibitor Wnt activation; stemness marker expression; protein synthesis assays Stem cell research Medium 34399164
2025 Cell-type-specific Eif2b5 conditional mouse models reveal that oligodendrocyte-specific Eif2b5 mutation is the primary driver of ataxia and myelination defects in VWM, while astrocyte-specific Eif2b5 mutation drives intramyelinic vacuolization and ATF4-related gene expression with only mild motor phenotype; neuronal Eif2b5 mutation produces very mild phenotype. Cell-type-specific conditional Eif2b5 mouse lines (astrocyte, oligodendrocyte, neuron Cre drivers); motor behavioral testing; neuropathology; IHC for myelin proteins, astrocyte/oligodendrocyte markers; ISR/ATF4 gene expression analysis Brain : a journal of neurology High 40326783
1987 Phosphorylation of eIF-2α prevents eIF-2B-mediated dissociation of eIF-2·GDP from the 60S ribosomal subunit of complete initiation complexes; exogenous eIF-2B restores this function in inhibited lysates, shifting complexes from half-mers back to actively elongating polysomes. Rabbit reticulocyte lysate; polysome fractionation; sucrose gradient sedimentation; addition of purified exogenous eIF-2B; Met-tRNA binding assays The Journal of biological chemistry Medium 3646234
1991 Purified eIF-2B requires Met-tRNA(fMet) to efficiently exchange GDP for GTP on eIF-2 under physiological conditions; tRNA(fMet) alone is ineffective, indicating that efficient recycling of eIF-2·GDP to eIF-2·GTP in vivo requires formation of the ternary Met-tRNA(fMet)·eIF-2·GTP complex to stabilize the product. In vitro GEF assays with purified eIF-2B, eIF-2, and tRNA components; comparison of GDP vs GTP exchange rates with/without Met-tRNA Biochemical and biophysical research communications Medium 1764100
2008 A splice site mutation in EIF2B5 exon 6 causes exon skipping, deleting part of the non-catalytic N-terminal domain of eIF2Bε; the truncated protein is undetectable, and eIF2B GEF activity is severely decreased, demonstrating that the non-catalytic domain of eIF2Bε is required for complex formation and activity. RT-PCR analysis of patient lymphoblastoid cell RNA; GEF activity assay in patient cells; protein expression analysis Annals of human genetics Medium 18294360
2022 LncRNA KCNQ1OT1 recruits DNA methyltransferases (DNMT1, DNMT3A, DNMT3B) to the EIF2B5 promoter, increasing its methylation and suppressing EIF2B5 expression in ovarian cancer cells; EIF2B5 silencing rescues the anti-tumor effects of KCNQ1OT1 depletion. MS-PCR for EIF2B5 promoter methylation; RIP and ChIP assays for DNMT binding; dual luciferase reporter assay; siRNA knockdown rescue experiments Molecular medicine Medium 36100884
2025 EIF2B5 directly interacts with ribosomal protein RPL6 (identified by mass spectrometry and co-immunoprecipitation) in hepatocellular carcinoma cells; EIF2B5 overexpression promotes RPL6 expression and activates the PI3K/AKT/mTOR pathway. Mass spectrometry after immunoprecipitation; co-IP validation; Western blotting; siRNA knockdown; mouse ectopic tumor assay Cellular signalling Low 40246131

Source papers

Stage 0 corpus · 71 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1993 Glycogen synthase kinase-3 is rapidly inactivated in response to insulin and phosphorylates eukaryotic initiation factor eIF-2B. The Biochemical journal 349 8397507
2001 The kinase DYRK phosphorylates protein-synthesis initiation factor eIF2Bepsilon at Ser539 and the microtubule-associated protein tau at Thr212: potential role for DYRK as a glycogen synthase kinase 3-priming kinase. The Biochemical journal 268 11311121
1992 Phosphorylation of eukaryotic initiation factor (eIF) 2 alpha and inhibition of eIF-2B in GH3 pituitary cells by perturbants of early protein processing that induce GRP78. The Journal of biological chemistry 116 1512215
1995 Modulation of tRNA(iMet), eIF-2, and eIF-2B expression shows that GCN4 translation is inversely coupled to the level of eIF-2.GTP.Met-tRNA(iMet) ternary complexes. Molecular and cellular biology 112 7565788
2005 EIF2B5 mutations compromise GFAP+ astrocyte generation in vanishing white matter leukodystrophy. Nature medicine 109 15723074
2002 Cree leukoencephalopathy and CACH/VWM disease are allelic at the EIF2B5 locus. Annals of neurology 104 12325082
1994 The guanine nucleotide-exchange factor, eIF-2B. Biochimie 89 7893825
2000 Identification of domains and residues within the epsilon subunit of eukaryotic translation initiation factor 2B (eIF2Bepsilon) required for guanine nucleotide exchange reveals a novel activation function promoted by eIF2B complex formation. Molecular and cellular biology 84 10805739
2016 GSK3β regulates AKT-induced central nervous system axon regeneration via an eIF2Bε-dependent, mTORC1-independent pathway. eLife 74 26974342
1996 Glucose stimulates the activity of the guanine nucleotide-exchange factor eIF-2B in isolated rat islets of Langerhans. The Journal of biological chemistry 73 8567668
2008 Resistance exercise decreases eIF2Bepsilon phosphorylation and potentiates the feeding-induced stimulation of p70S6K1 and rpS6 in young men. American journal of physiology. Regulatory, integrative and comparative physiology 63 18565837
1994 Purification and characterization of eukaryotic translational initiation factor eIF-2B from liver. Biochimica et biophysica acta 56 7803480
2004 Arg113His mutation in eIF2Bepsilon as cause of leukoencephalopathy in adults. Neurology 55 15136689
1994 Mutations in the GCD7 subunit of yeast guanine nucleotide exchange factor eIF-2B overcome the inhibitory effects of phosphorylated eIF-2 on translation initiation. Molecular and cellular biology 52 8164676
1994 Use of monoclonal antibodies to study the structure and function of eukaryotic protein synthesis initiation factor eIF-2B. European journal of biochemistry 48 8168527
2004 Adult-onset leukoencephalopathy with vanishing white matter with a missense mutation in EIF2B5. Neurology 46 15136690
1994 Expression of mutant eukaryotic initiation factor 2 alpha subunit (eIF-2 alpha) reduces inhibition of guanine nucleotide exchange activity of eIF-2B mediated by eIF-2 alpha phosphorylation. Molecular and cellular biology 41 8007958
2017 Transcriptome analysis of hypoxic cancer cells uncovers intron retention in EIF2B5 as a mechanism to inhibit translation. PLoS biology 40 28961236
2002 Evidence that the dephosphorylation of Ser(535) in the epsilon-subunit of eukaryotic initiation factor (eIF) 2B is insufficient for the activation of eIF2B by insulin. The Biochemical journal 40 12133000
1987 Evidence that phosphorylation of eIF-2(alpha) prevents the eIF-2B-mediated dissociation of eIF-2 X GDP from the 60 S subunit of complete initiation complexes. The Journal of biological chemistry 35 3646234
1988 Regulation of protein synthesis in rabbit reticulocyte lysate. Glucose 6-phosphate is required to maintain the activity of eukaryotic initiation factor (eIF)-2B by a mechanism that is independent of the phosphorylation of eIF-2 alpha. The Journal of biological chemistry 33 2842334
1984 The association of eIF-2 with Met-tRNAi or eIF-2B alters the specificity of eIF-2 phosphatase. The Journal of biological chemistry 25 6088496
2010 Epigenetic control of translation regulation: alterations in histone H3 lysine 9 post-translation modifications are correlated with the expression of the translation initiation factor 2B (Eif2b5) during thermal control establishment. Developmental neurobiology 24 19950192
2022 LncRNA KCNQ1OT1 promotes the metastasis of ovarian cancer by increasing the methylation of EIF2B5 promoter. Molecular medicine (Cambridge, Mass.) 23 36100884
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