id: Q9UI10
gene_symbol: EIF2B4
product_type: PROTEIN
taxon:
  id: NCBITaxon:9606
  label: Homo sapiens
description: >-
  EIF2B4 encodes the delta subunit of eukaryotic translation initiation factor 2B (eIF2B),
  a heterodecameric guanine nucleotide exchange factor (GEF) essential for translation initiation.
  The delta subunit, together with alpha and beta subunits, forms the regulatory subcomplex that
  senses cellular stress signals, particularly through binding phosphorylated eIF2alpha. The
  eIF2B complex catalyzes GDP-GTP exchange on eIF2, regenerating active eIF2-GTP complexes
  required for continued protein synthesis. EIF2B4 is critical for the integrated stress response
  (ISR), where phosphorylated eIF2alpha binds at the interface between eIF2Balpha and eIF2Bdelta
  subunits, inhibiting GEF activity and reducing global translation. eIF2Bdelta is a regulatory/scaffold
  (noncatalytic) subunit that contributes to decameric holoenzyme assembly and is part of the
  beta/delta core that supports allosteric regulation by small molecules such as ISRIB. In mammalian
  cells, eIF2B (including the delta subunit) localizes to discrete cytoplasmic "eIF2B bodies"
  whose subunit composition is cell-type specific and which represent sites of GEF activity
  (PMID:39310746). Mutations in EIF2B4 cause vanishing white matter disease (leukoencephalopathy
  with VWM) and ovarioleukodystrophy, demonstrating the essential role of this subunit in normal
  eIF2B function, particularly in oligodendrocytes and astrocytes.
existing_annotations:
- term:
    id: GO:0002183
    label: cytoplasmic translational initiation
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    summary: >-
      EIF2B4 is part of the eIF2B complex that functions in the cytoplasm to catalyze
      GDP-GTP exchange on eIF2, which is essential for cytoplasmic translation initiation.
      This annotation is well-supported by phylogenetic analysis and the deep research
      showing eIF2B is a cytosolic complex essential for translation initiation [PMID:11323413].
    action: ACCEPT
    reason: >-
      The IBA annotation is appropriate. EIF2B4 is a component of the eIF2B complex, which
      is the sole GEF for eIF2 and is required for cytoplasmic translation initiation.
      The deep research confirms "eIF2B serves as the sole guanine nucleotide exchange factor
      (GEF) for eIF2, playing a pivotal role in recycling eIF2 for continued protein synthesis."
    supported_by:
    - reference_id: PMID:11323413
      supporting_text: "Initiation factor eIF2B mediates a key regulatory step in the initiation of mRNA translation, i.e. the regeneration of active eIF2.GTP complexes."
    - reference_id: file:human/EIF2B4/EIF2B4-deep-research-openai.md
      supporting_text: "eIF2B serves as the sole guanine nucleotide exchange factor (GEF) for eIF2, playing a pivotal role in recycling eIF2 for continued protein synthesis"
- term:
    id: GO:0005851
    label: eukaryotic translation initiation factor 2B complex
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    summary: >-
      EIF2B4 encodes the delta subunit of the eIF2B complex, which is a heterodecameric
      assembly. The delta subunit is part of the regulatory subcomplex along with alpha
      and beta subunits. Cryo-EM structures have confirmed the architecture of the
      complex [PMID:29599213].
    action: ACCEPT
    reason: >-
      The delta subunit is a core component of the eIF2B complex. UniProt confirms
      "Component of the translation initiation factor 2B (eIF2B) complex which is a
      heterodecamer of two sets of five different subunits: alpha, beta, gamma, delta
      and epsilon."
    supported_by:
    - reference_id: PMID:29599213
      supporting_text: "Formation of fully active, decameric eIF2B holoenzyme depended on the assembly of two identical tetrameric subcomplexes"
    - reference_id: PMID:11323413
      supporting_text: "It is composed of five subunits, alpha-epsilon."
    - reference_id: PMID:24532666
      supporting_text: "Analysis of the subunit organization of the eIF2B complex reveals new insights into its structure and regulation"
    - reference_id: file:human/EIF2B4/EIF2B4-deep-research-falcon.md
      supporting_text: "eIF2B is a decamer composed of two copies of each of five subunits (α–ε) and place δ (EIF2B4) among the regulatory subunits (α/β/δ) rather than the catalytic subunits (γ/ε)"
- term:
    id: GO:0003743
    label: translation initiation factor activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000043
  review:
    summary: >-
      This IEA annotation from UniProtKB keyword mapping is appropriate as EIF2B4 is
      part of eIF2B, which functions as a translation initiation factor by regenerating
      active eIF2-GTP complexes needed for translation initiation [PMID:16289705].
    action: ACCEPT
    reason: >-
      EIF2B4 as part of the eIF2B complex contributes to translation initiation factor
      activity. PMID:16289705 demonstrates that "eIF2 and eIF2B augmented translation"
      in cell-free systems, confirming the translation initiation factor activity.
      Note that EIF2B4 itself does not have direct catalytic activity (catalytic core
      is in epsilon/gamma subunits) but contributes to the overall activity of the complex.
    supported_by:
    - reference_id: PMID:16289705
      supporting_text: "eIF2 (eukaryotic translation initiation factor 2) and eIF2B augmented translation of capped, uncapped and encephalomyocarditis virus-internal ribosome entry site-promoted mRNAs."
- term:
    id: GO:0005085
    label: guanyl-nucleotide exchange factor activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000117
  review:
    summary: >-
      The eIF2B complex has GEF activity, catalyzing GDP-GTP exchange on eIF2.
      While the catalytic activity resides primarily in the epsilon subunit, the
      delta subunit is required for full GEF activity as part of the regulatory
      subcomplex.
    action: ACCEPT
    reason: >-
      The IEA annotation correctly identifies that the eIF2B complex has GEF activity.
      PMID:11323413 directly characterizes "the mammalian initiation factor eIF2B complex
      as a GDP dissociation stimulator protein." The delta subunit contributes to
      this activity as part of the holoenzyme.
    supported_by:
    - reference_id: PMID:11323413
      supporting_text: "mammalian eIF2B can mediate release of eIF2-bound GDP even in the absence of free nucleotide, indicating that it acts as a GDP dissociation stimulator protein"
    - reference_id: file:human/EIF2B4/EIF2B4-deep-research-falcon.md
      supporting_text: "eIF2B is the GEF for eIF2, recycling inactive eIF2–GDP to active eIF2–GTP, thereby replenishing the pool of eIF2 needed to form the ternary complex (eIF2–GTP·Met-tRNAi) and initiate translation"
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  review:
    summary: >-
      EIF2B4 localizes to the cytosol as part of the eIF2B complex, where translation
      initiation occurs. Deep research confirms "The EIF2B4 gene product (eIF2Bdelta)
      carries out its function in the cytosol, where translation initiation occurs."
      Recent work shows eIF2B localizes to discrete cytoplasmic eIF2B bodies (sites of
      GEF activity) with cell-type-specific composition including the delta subunit
      (PMID:39310746).
    action: ACCEPT
    reason: >-
      The cytosolic localization is well-established for eIF2B subunits. UniProt
      annotation states "Cytoplasm, cytosol" with ECO:0000250 evidence from S. pombe
      ortholog. This is consistent with the function in cytoplasmic translation initiation.
    supported_by:
    - reference_id: file:human/EIF2B4/EIF2B4-deep-research-openai.md
      supporting_text: "The EIF2B4 gene product (eIF2Bdelta) carries out its function in the cytosol, where translation initiation occurs."
    - reference_id: PMID:39310746
      supporting_text: "eIF2B localization and its regulation during the integrated stress response is cell-type specific"
- term:
    id: GO:0005851
    label: eukaryotic translation initiation factor 2B complex
  evidence_type: IEA
  original_reference_id: GO_REF:0000117
  review:
    summary: >-
      Duplicate annotation (different evidence source from IBA above) confirming
      EIF2B4 as a component of the eIF2B complex.
    action: ACCEPT
    reason: >-
      This IEA annotation reinforces that EIF2B4 is part of the eIF2B complex.
      Multiple evidence lines supporting the same conclusion is appropriate.
    supported_by:
    - reference_id: PMID:29599213
      supporting_text: "Formation of fully active, decameric eIF2B holoenzyme depended on the assembly of two identical tetrameric subcomplexes"
- term:
    id: GO:0006412
    label: translation
  evidence_type: IEA
  original_reference_id: GO_REF:0000043
  review:
    summary: >-
      EIF2B4 is involved in translation as part of the eIF2B complex, which is
      essential for regenerating active eIF2-GTP complexes required for translation
      initiation.
    action: ACCEPT
    reason: >-
      The involvement in translation is well-established. The deep research states
      "eIF2B serves as the sole guanine nucleotide exchange factor (GEF) for eIF2,
      playing a pivotal role in recycling eIF2 for continued protein synthesis."
      GO:0006413 (translational initiation) would be more specific, but this parent
      term is also accurate.
    supported_by:
    - reference_id: PMID:16289705
      supporting_text: "eIF2 (eukaryotic translation initiation factor 2) and eIF2B augmented translation of capped, uncapped and encephalomyocarditis virus-internal ribosome entry site-promoted mRNAs."
- term:
    id: GO:0006413
    label: translational initiation
  evidence_type: IEA
  original_reference_id: GO_REF:0000043
  review:
    summary: >-
      EIF2B4 is involved in translational initiation as part of the eIF2B complex,
      which regenerates eIF2-GTP needed for initiating translation of mRNAs.
    action: ACCEPT
    reason: >-
      The role in translational initiation is directly supported by literature.
      PMID:11323413 states "Initiation factor eIF2B mediates a key regulatory step
      in the initiation of mRNA translation."
    supported_by:
    - reference_id: PMID:11323413
      supporting_text: "Initiation factor eIF2B mediates a key regulatory step in the initiation of mRNA translation, i.e. the regeneration of active eIF2.GTP complexes."
- term:
    id: GO:0007417
    label: central nervous system development
  evidence_type: IEA
  original_reference_id: GO_REF:0000117
  review:
    summary: >-
      This annotation is derived from ARBA machine learning. While EIF2B4 mutations
      cause vanishing white matter disease affecting the CNS, the role of EIF2B4 in
      CNS development is indirect - through its essential role in translation rather
      than a specific developmental function.
    action: KEEP_AS_NON_CORE
    reason: >-
      EIF2B4 is essential for protein synthesis, which is required for all developmental
      processes. The CNS is particularly sensitive to EIF2B deficiency as shown in VWM
      disease, but this reflects the high protein synthesis demands of oligodendrocytes
      rather than a specific developmental role. This is a pleiotropic/secondary effect
      rather than a core function.
    supported_by:
    - reference_id: PMID:15217090
      supporting_text: "Vanishing white matter disease (VWM) is a progressive cavitating disease of central white matter due to a deficiency of the translation initiation factor eIF2B."
- term:
    id: GO:0048513
    label: animal organ development
  evidence_type: IEA
  original_reference_id: GO_REF:0000117
  review:
    summary: >-
      This IEA annotation is too general and reflects the essential nature of
      protein synthesis (requiring eIF2B) for all developmental processes rather
      than a specific function of EIF2B4.
    action: REMOVE
    reason: >-
      This is an over-annotation. EIF2B4 is essential for global protein synthesis,
      which is required for all cellular processes including organ development.
      However, there is no evidence that EIF2B4 plays a specific role in organ
      development beyond enabling general translation. The annotation is too broad
      and not informative for this gene.
    supported_by:
    - reference_id: file:human/EIF2B4/EIF2B4-deep-research-openai.md
      supporting_text: "eIF2B serves as the sole guanine nucleotide exchange factor (GEF) for eIF2, playing a pivotal role in recycling eIF2 for continued protein synthesis"
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:25416956
  review:
    summary: >-
      Generic protein binding annotation from high-throughput interactome mapping.
      EIF2B4 binds to EIF2B2 as part of the eIF2B complex.
    action: REMOVE
    reason: >-
      GO curation guidelines discourage use of the generic "protein binding" term
      when more specific terms are available. The interaction with EIF2B2 is better
      captured by the eIF2B complex membership annotation (GO:0005851). More specific
      terms like "translation initiation factor binding" (GO:0031369) are also annotated.
    supported_by:
    - reference_id: PMID:25416956
      supporting_text: "A proteome-scale map of the human interactome network"
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:25910212
  review:
    summary: >-
      High-throughput interaction study showing EIF2B4 interacts with EIF2B2.
    action: REMOVE
    reason: >-
      The generic "protein binding" term is not informative. The interaction between
      EIF2B4 and EIF2B2 is well-characterized as part of the eIF2B complex structure.
      This is better represented by the complex membership annotation.
    supported_by:
    - reference_id: PMID:25910212
      supporting_text: "Widespread macromolecular interaction perturbations in human genetic disorders"
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:28169297
  review:
    summary: >-
      This study identified interactions between influenza viral proteins and host
      proteins including EIF2B4. The biological significance of these interactions
      to EIF2B4's core function is unclear.
    action: REMOVE
    reason: >-
      Generic protein binding is uninformative. The viral protein interactions may
      represent viral hijacking of the translation machinery but do not inform about
      EIF2B4's core molecular function.
    supported_by:
    - reference_id: PMID:28169297
      supporting_text: "Comparative influenza protein interactomes identify the role of plakophilin 2 in virus restriction"
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:29599245
  review:
    summary: >-
      Study examining binding of ISRIB to eIF2B complex including EIF2B4.
    action: REMOVE
    reason: >-
      The generic "protein binding" term does not capture the functional relevance.
      The ISRIB binding affects eIF2B activity but is better understood in the
      context of GEF activity regulation. The small molecule binding is not well
      captured by "protein binding."
    supported_by:
    - reference_id: PMID:29599245
      supporting_text: "Binding of ISRIB reveals a regulatory site in the nucleotide exchange factor eIF2B"
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:31515488
  review:
    summary: >-
      High-throughput study on protein-protein interactions across human populations.
    action: REMOVE
    reason: >-
      Generic protein binding annotation from high-throughput study is not informative.
      More specific molecular function terms are available.
    supported_by:
    - reference_id: PMID:31515488
      supporting_text: "Extensive disruption of protein interactions by genetic variants across the allele frequency spectrum in human populations"
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:32296183
  review:
    summary: >-
      Human binary interactome mapping study.
    action: REMOVE
    reason: >-
      Generic protein binding from high-throughput interactome study is not informative
      for annotation purposes. The specific interactions of EIF2B4 within the eIF2B
      complex and with eIF2 are better captured by other annotations.
    supported_by:
    - reference_id: PMID:32296183
      supporting_text: "A reference map of the human binary protein interactome"
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:32814053
  review:
    summary: >-
      Study on interactome mapping in neurodegenerative disease.
    action: REMOVE
    reason: >-
      Generic protein binding is not informative. While EIF2B4 mutations cause
      neurodegeneration, the relevant molecular function is its role in the eIF2B
      complex with GEF activity, not generic protein binding.
    supported_by:
    - reference_id: PMID:32814053
      supporting_text: "Interactome Mapping Provides a Network of Neurodegenerative Disease Proteins and Uncovers Widespread Protein Aggregation in Affected Brains"
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:33961781
  review:
    summary: >-
      Dual proteome-scale network study on cell-specific interactomes.
    action: REMOVE
    reason: >-
      Generic protein binding is uninformative. Better molecular function terms exist.
    supported_by:
    - reference_id: PMID:33961781
      supporting_text: "Dual proteome-scale networks reveal cell-specific remodeling of the human interactome"
- term:
    id: GO:0005851
    label: eukaryotic translation initiation factor 2B complex
  evidence_type: IPI
  original_reference_id: PMID:29599213
  review:
    summary: >-
      Cryo-EM structural study demonstrating EIF2B4 (delta subunit) is part of the
      eIF2B decameric complex. This study solved the atomic structure of the complex.
    action: ACCEPT
    reason: >-
      Excellent experimental evidence from structural studies. PMID:29599213 states
      "Formation of fully active, decameric eIF2B holoenzyme depended on the assembly
      of two identical tetrameric subcomplexes."
    supported_by:
    - reference_id: PMID:29599213
      supporting_text: "we solved an atomic-resolution structure of ISRIB bound in a deep cleft within decameric human eIF2B by cryo-electron microscopy"
- term:
    id: GO:0045948
    label: positive regulation of translational initiation
  evidence_type: IDA
  original_reference_id: PMID:29599213
  review:
    summary: >-
      The eIF2B complex positively regulates translation initiation by catalyzing
      GDP-GTP exchange on eIF2, thereby regenerating active eIF2-GTP complexes.
    action: ACCEPT
    reason: >-
      This annotation correctly captures the regulatory role of eIF2B. The deep
      research confirms that "eIF2B enables continuous rounds of translation initiation"
      by recycling eIF2-GDP to eIF2-GTP.
    supported_by:
    - reference_id: PMID:29599213
      supporting_text: "Formation of fully active, decameric eIF2B holoenzyme depended on the assembly of two identical tetrameric subcomplexes"
    - reference_id: file:human/EIF2B4/EIF2B4-deep-research-openai.md
      supporting_text: "By recycling eIF2-GDP to eIF2-GTP, eIF2B enables continuous rounds of translation initiation"
- term:
    id: GO:0002183
    label: cytoplasmic translational initiation
  evidence_type: IDA
  original_reference_id: PMID:27023709
  review:
    summary: >-
      Study on expression and crystallization of S. pombe eIF2B, providing functional
      evidence for the role of eIF2B subunits in cytoplasmic translation initiation.
    action: ACCEPT
    reason: >-
      EIF2B4 is part of the eIF2B complex essential for cytoplasmic translation initiation.
      The IDA evidence from this study supports the annotation.
    supported_by:
    - reference_id: PMID:27023709
      supporting_text: "Expression, purification, and crystallization of Schizosaccharomyces pombe eIF2B"
- term:
    id: GO:0005085
    label: guanyl-nucleotide exchange factor activity
  evidence_type: IDA
  original_reference_id: PMID:25858979
  review:
    summary: >-
      This landmark study identified the target of ISRIB (a memory-enhancing compound)
      as eIF2B and confirmed the GEF activity of the complex. Mutations in the delta
      subunit affected ISRIB's stimulatory effect on eIF2B GEF activity.
    action: ACCEPT
    reason: >-
      Strong experimental evidence. The study states that ISRIB affected "its stimulatory
      effect on eIF2B GEF activity toward its substrate, the translation initiation
      factor eIF2, in vitro." Mutations in the delta subunit affected this activity,
      demonstrating EIF2B4's contribution to GEF function.
    supported_by:
    - reference_id: PMID:25858979
      supporting_text: "these mutations reversed both ISRIB-mediated inhibition of the ISR and its stimulatory effect on eIF2B GEF activity toward its substrate, the translation initiation factor eIF2, in vitro"
- term:
    id: GO:0005085
    label: guanyl-nucleotide exchange factor activity
  evidence_type: IDA
  original_reference_id: PMID:27023709
  review:
    summary: >-
      Study providing functional evidence for eIF2B GEF activity through structural
      and biochemical characterization.
    action: ACCEPT
    reason: >-
      Multiple lines of evidence confirm eIF2B's GEF activity. This annotation is
      consistent with the well-established function of the eIF2B complex.
    supported_by:
    - reference_id: PMID:27023709
      supporting_text: "Expression, purification, and crystallization of Schizosaccharomyces pombe eIF2B"
- term:
    id: GO:0005851
    label: eukaryotic translation initiation factor 2B complex
  evidence_type: IDA
  original_reference_id: PMID:27023709
  review:
    summary: >-
      Direct evidence for EIF2B4 as a component of the eIF2B complex from
      crystallization studies.
    action: ACCEPT
    reason: >-
      Strong experimental evidence from structural studies confirming the delta
      subunit's membership in the eIF2B complex.
    supported_by:
    - reference_id: PMID:27023709
      supporting_text: "Expression, purification, and crystallization of Schizosaccharomyces pombe eIF2B"
- term:
    id: GO:0050852
    label: T cell receptor signaling pathway
  evidence_type: IDA
  original_reference_id: PMID:8626696
  review:
    summary: >-
      Study showing that T-cell activation leads to rapid stimulation of eIF2B
      activity and inactivation of GSK-3. The eIF2B activity increases within 5
      minutes of T-cell stimulation.
    action: KEEP_AS_NON_CORE
    reason: >-
      This annotation reflects that eIF2B is regulated downstream of T-cell receptor
      signaling through GSK-3 inactivation, rather than EIF2B4 having a direct role
      in TCR signaling itself. The study states "The rapid activation of EIF2B
      following mitogenic stimulation of T-cells is therefore mediated by factors
      other than its own concentration." This is a regulatory context rather than
      a direct signaling function.
    supported_by:
    - reference_id: PMID:8626696
      supporting_text: "Mitogenic stimulation of T-lymphocytes causes a rapid activation or protein synthesis... eIF2B activity rises quickly, increasing as early as 5 min after cell stimulation"
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-72670
  review:
    summary: >-
      Reactome pathway annotation for formation of eIF2:GDP:eIF2B intermediate,
      which occurs in the cytosol.
    action: ACCEPT
    reason: >-
      The cytosolic localization is consistent with the function in translation
      initiation, which occurs in the cytoplasm.
    supported_by:
    - reference_id: Reactome:R-HSA-72670
      supporting_text: "Formation of eIF2:GDP:eIF2B intermediate"
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-72722
  review:
    summary: >-
      Reactome pathway annotation for eIF2 activation, which occurs in the cytosol.
    action: ACCEPT
    reason: >-
      Consistent with cytosolic localization for translation initiation function.
    supported_by:
    - reference_id: file:human/EIF2B4/EIF2B4-deep-research-openai.md
      supporting_text: "The EIF2B4 gene product (eIF2Bdelta) carries out its function in the cytosol, where translation initiation occurs."
- term:
    id: GO:0031369
    label: translation initiation factor binding
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  review:
    summary: >-
      EIF2B4 binds to eIF2 (the substrate of the eIF2B complex) as part of the
      nucleotide exchange mechanism. This is inferred from sequence similarity
      to rat ortholog.
    action: ACCEPT
    reason: >-
      The deep research confirms that "eIF2 binds across the decameric interface,
      engaging the eIF2B alpha subunit, and beta and delta subunits" (PMID:29599213).
      This directly demonstrates translation initiation factor binding by EIF2B4.
    supported_by:
    - reference_id: PMID:29599213
      supporting_text: "eIF2 binds across the decameric interface, engaging the eIF2B alpha subunit, and beta and delta subunits from opposing tetramers"
- term:
    id: GO:0006413
    label: translational initiation
  evidence_type: IDA
  original_reference_id: PMID:16289705
  review:
    summary: >-
      Study demonstrating that supplementation with eIF2B enhances translation in
      mammalian cell-free systems.
    action: ACCEPT
    reason: >-
      Direct experimental evidence showing that eIF2B augments translation.
      The study states "eIF2 and eIF2B augmented translation of capped, uncapped
      and encephalomyocarditis virus-internal ribosome entry site-promoted mRNAs."
    supported_by:
    - reference_id: PMID:16289705
      supporting_text: "eIF2 (eukaryotic translation initiation factor 2) and eIF2B augmented translation of capped, uncapped and encephalomyocarditis virus-internal ribosome entry site-promoted mRNAs."
- term:
    id: GO:0009408
    label: response to heat
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  review:
    summary: >-
      EIF2B is regulated as part of the integrated stress response, which includes
      heat stress. Inferred from sequence similarity to rat ortholog.
    action: KEEP_AS_NON_CORE
    reason: >-
      EIF2B4 is part of the eIF2B complex that is regulated during the integrated
      stress response. Heat stress causes eIF2alpha phosphorylation, which inhibits
      eIF2B activity. This is a response to stress rather than a core function.
      The deep research confirms "In response to various stresses (e.g. nutrient
      starvation, viral infection, ER stress), specialized kinases... phosphorylate
      eIF2 on its alpha subunit."
    supported_by:
    - reference_id: file:human/EIF2B4/EIF2B4-deep-research-openai.md
      supporting_text: "In response to various stresses (e.g. nutrient starvation, viral infection, ER stress), specialized kinases such as PKR, GCN2, PERK, and HRI phosphorylate eIF2 on its alpha subunit at Ser51"
- term:
    id: GO:0009408
    label: response to heat
  evidence_type: TAS
  original_reference_id: PMID:12499492
  review:
    summary: >-
      Study describing vanishing white matter disease related to EIF2B5 mutation,
      noting that fever (heat stress) triggers neurological deterioration.
    action: KEEP_AS_NON_CORE
    reason: >-
      Heat stress triggers the integrated stress response, which modulates eIF2B
      activity. This is a regulatory context rather than a direct function of EIF2B4.
      In VWM patients, "additional episodes of rapid deterioration following febrile
      infections" are common, demonstrating that heat/fever affects eIF2B-dependent
      cells.
    supported_by:
    - reference_id: PMID:12499492
      supporting_text: "A severe variant of childhood ataxia with central hypomyelination/vanishing white matter leukoencephalopathy related to EIF21B5 mutation"
- term:
    id: GO:0014003
    label: oligodendrocyte development
  evidence_type: IMP
  original_reference_id: PMID:15217090
  review:
    summary: >-
      Study on vanishing white matter disease showing that oligodendrocytes are
      affected by eIF2B deficiency. The study documents increased oligodendrocyte
      density with evidence of both apoptosis and proliferation.
    action: KEEP_AS_NON_CORE
    reason: >-
      The phenotype in VWM disease reflects the high protein synthesis demands of
      oligodendrocytes, making them particularly sensitive to eIF2B deficiency.
      This is a secondary/pleiotropic effect of impaired translation rather than
      a specific developmental role. The study states "Vanishing white matter
      disease (VWM) is a progressive cavitating disease of central white matter
      due to a deficiency of the translation initiation factor eIF2B."
    supported_by:
    - reference_id: PMID:15217090
      supporting_text: "Vanishing white matter disease (VWM) is a progressive cavitating disease of central white matter due to a deficiency of the translation initiation factor eIF2B. Oligodendrocytes appear to be numerically increased in some white matter areas, while decreased in others."
- term:
    id: GO:0003743
    label: translation initiation factor activity
  evidence_type: IDA
  original_reference_id: PMID:16289705
  review:
    summary: >-
      Direct experimental evidence showing eIF2B enhances translation in cell-free
      systems. The annotation uses "contributes_to" qualifier, which is appropriate
      since the catalytic activity is primarily in the epsilon subunit.
    action: ACCEPT
    reason: >-
      This annotation correctly captures that EIF2B4 contributes to (rather than
      directly enables) translation initiation factor activity as part of the
      eIF2B complex. The catalytic core is in epsilon/gamma subunits, but the
      delta subunit is required for full activity.
    supported_by:
    - reference_id: PMID:16289705
      supporting_text: "eIF2 (eukaryotic translation initiation factor 2) and eIF2B augmented translation of capped, uncapped and encephalomyocarditis virus-internal ribosome entry site-promoted mRNAs."
- term:
    id: GO:0009749
    label: response to glucose
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  review:
    summary: >-
      eIF2B activity is regulated by metabolic signals including glucose levels,
      through insulin signaling and GSK-3 phosphorylation of eIF2Bepsilon.
    action: KEEP_AS_NON_CORE
    reason: >-
      eIF2B is regulated by metabolic signals but this is not a core function.
      The deep research notes that "insulin signaling blocks GSK-3, leading to
      Ser535 dephosphorylation and enhanced eIF2B function." This represents
      regulation of eIF2B activity by metabolic state rather than a direct
      response to glucose by EIF2B4.
    supported_by:
    - reference_id: file:human/EIF2B4/EIF2B4-deep-research-openai.md
      supporting_text: "insulin - through the PI3K/Akt pathway - activates eIF2B by inhibiting GSK-3 kinase"
- term:
    id: GO:0043434
    label: response to peptide hormone
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  review:
    summary: >-
      eIF2B activity is modulated by insulin (a peptide hormone) through the
      GSK-3 pathway. Inferred from sequence similarity to rat ortholog.
    action: KEEP_AS_NON_CORE
    reason: >-
      eIF2B is regulated downstream of insulin signaling, but this is a
      regulatory context rather than a core function of EIF2B4. The annotation
      reflects that eIF2B is part of a pathway responding to peptide hormones
      rather than directly sensing them.
    supported_by:
    - reference_id: PMID:8626696
      supporting_text: "The largest (epsilon) subunit of eIF2B is a substrate for glycogen synthase kinase-3 (GSK-3), the activity of which rapidly decreases following T-cell activation."
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:15060152
  review:
    summary: >-
      Study examining mutations linked to vanishing white matter disease and their
      effects on eIF2B complex function and interactions with EIF2B2.
    action: REMOVE
    reason: >-
      Generic protein binding is not informative. The relevant interaction (with
      EIF2B2 and other eIF2B subunits) is better captured by the eIF2B complex
      membership annotation.
    supported_by:
    - reference_id: PMID:15060152
      supporting_text: "Mutations linked to leukoencephalopathy with vanishing white matter impair the function of the eukaryotic initiation factor 2B complex in diverse ways"
- term:
    id: GO:0001541
    label: ovarian follicle development
  evidence_type: IMP
  original_reference_id: PMID:15507143
  review:
    summary: >-
      Study screening for EIF2B mutations in patients with premature ovarian failure.
      Some EIF2B4 mutations cause ovarioleukodystrophy.
    action: KEEP_AS_NON_CORE
    reason: >-
      The ovarian phenotype in VWM/ovarioleukodystrophy reflects the sensitivity
      of rapidly dividing cells to translation defects. UniProt notes that mutations
      cause "ovarian failure" and "ovarioleukodystrophy." However, this is a
      secondary effect of impaired global translation rather than a specific
      role in ovarian development.
    supported_by:
    - reference_id: PMID:15507143
      supporting_text: "Screening for known mutations in EIF2B genes in a large panel of patients with premature ovarian failure"
    - reference_id: PMID:39139316
      supporting_text: "This resulted in a series of 20 cases of women with ovarioleukodystrophy due to variants in the EIF2B gene complex. The median age of onset was 19 years (range 0.6-40). The clinical features present in the entire sample were WM involvement and ovarian changes, the latter corresponding to ovarian dysgenesis (5%), primary amenorrhea (15%), secondary amenorrhea (15%), and premature ovarian failure (60%)"
- term:
    id: GO:0005085
    label: guanyl-nucleotide exchange factor activity
  evidence_type: IDA
  original_reference_id: PMID:11323413
  review:
    summary: >-
      Seminal study characterizing mammalian eIF2B as a GDP dissociation stimulator
      protein. Demonstrated that eIF2B can mediate release of eIF2-bound GDP.
    action: ACCEPT
    reason: >-
      Strong experimental evidence. The study directly demonstrates GEF activity:
      "mammalian eIF2B can mediate release of eIF2-bound GDP even in the absence
      of free nucleotide, indicating that it acts as a GDP dissociation stimulator
      protein." Note: the annotation uses "contributes_to" qualifier, which is
      appropriate as catalytic activity is primarily in epsilon subunit.
    supported_by:
    - reference_id: PMID:11323413
      supporting_text: "mammalian eIF2B can mediate release of eIF2-bound GDP even in the absence of free nucleotide, indicating that it acts as a GDP dissociation stimulator protein"
    - reference_id: file:human/EIF2B4/EIF2B4-deep-research-falcon.md
      supporting_text: "eIF2B's catalytic function is mainly attributed to the γ and ε subunits, while α/β/δ enhance full activity and provide regulatory control, including stress sensitivity"
- term:
    id: GO:0005737
    label: cytoplasm
  evidence_type: IDA
  original_reference_id: PMID:11323413
  review:
    summary: >-
      Study demonstrating eIF2B function in the cytoplasm through biochemical
      characterization of the complex.
    action: ACCEPT
    reason: >-
      The cytoplasmic localization is well-established and consistent with the
      function in translation initiation, which occurs in the cytoplasm.
    supported_by:
    - reference_id: PMID:11323413
      supporting_text: "Characterization of the mammalian initiation factor eIF2B complex as a GDP dissociation stimulator protein"
- term:
    id: GO:0005851
    label: eukaryotic translation initiation factor 2B complex
  evidence_type: IDA
  original_reference_id: PMID:11323413
  review:
    summary: >-
      Study characterizing the five-subunit eIF2B complex, confirming EIF2B4
      (delta) as a component.
    action: ACCEPT
    reason: >-
      Direct experimental evidence. The study states "It is composed of five
      subunits, alpha-epsilon."
    supported_by:
    - reference_id: PMID:11323413
      supporting_text: "It is composed of five subunits, alpha-epsilon."
    - reference_id: PMID:24532666
      supporting_text: "is actually decameric, a dimer of eIF2B(βγδε) tetramers stabilized by 2 copies"
- term:
    id: GO:0042552
    label: myelination
  evidence_type: IMP
  original_reference_id: PMID:14566705
  review:
    summary: >-
      Study on eIF2B-related disorders showing that mutations cause myelination
      defects. Vanishing white matter disease involves loss of myelin.
    action: KEEP_AS_NON_CORE
    reason: >-
      The myelination phenotype in VWM reflects the high protein synthesis demands
      of myelinating oligodendrocytes. This is a secondary/pleiotropic effect of
      impaired translation rather than a direct role in myelination. The annotation
      is valid as a mutant phenotype but not a core function of EIF2B4.
    supported_by:
    - reference_id: PMID:14566705
      supporting_text: "eIF2B-related disorders: antenatal onset and involvement of multiple organs"
- term:
    id: GO:0005085
    label: guanyl-nucleotide exchange factor activity
  evidence_type: IMP
  original_reference_id: PMID:15054402
  review:
    summary: >-
      Study measuring GEF activity in cells from patients with eIF2B mutations.
      Demonstrated 20-70% decrease in GEF activity in mutated cells.
    action: ACCEPT
    reason: >-
      Strong functional evidence. The study states "A significant decrease of
      20-70% in GEF activity was observed in all mutated cells." This demonstrates
      that EIF2B4 mutations affect GEF activity. Uses "contributes_to" qualifier
      appropriately.
    supported_by:
    - reference_id: PMID:15054402
      supporting_text: "A significant decrease of 20-70% in GEF activity was observed in all mutated cells. The severity of this decrement of GEF activity correlated with age at onset of the disease."
- term:
    id: GO:0005851
    label: eukaryotic translation initiation factor 2B complex
  evidence_type: IDA
  original_reference_id: PMID:15060152
  review:
    summary: >-
      Study on mutations affecting eIF2B complex function, confirming EIF2B4
      as a component of the complex.
    action: ACCEPT
    reason: >-
      Direct experimental evidence from studies of the eIF2B complex.
    supported_by:
    - reference_id: PMID:15060152
      supporting_text: "Mutations linked to leukoencephalopathy with vanishing white matter impair the function of the eukaryotic initiation factor 2B complex in diverse ways"
- term:
    id: GO:0006417
    label: regulation of translation
  evidence_type: NAS
  original_reference_id: PMID:12556349
  review:
    summary: >-
      Study showing that reduced amino acid availability inhibits muscle protein
      synthesis and decreases eIF2B activity.
    action: ACCEPT
    reason: >-
      eIF2B is a key regulator of translation. The deep research confirms that
      "eIF2B activity is regulated during the integrated stress response" and
      "By assembling these subunits, eIF2B serves as the sole guanine nucleotide
      exchange factor (GEF) for eIF2, playing a pivotal role in recycling eIF2
      for continued protein synthesis."
    supported_by:
    - reference_id: PMID:12556349
      supporting_text: "Reduced amino acid availability inhibits muscle protein synthesis and decreases activity of initiation factor eIF2B"
    - reference_id: PMID:36943285
      supporting_text: "Phosphorylation of eIF2α (p-eIF2α) blocks the eIF2B-directed exchange, consequently reducing the levels of eIF2•GTP that are required for delivery of methionyl initiator tRNA"
    - reference_id: file:human/EIF2B4/EIF2B4-deep-research-falcon.md
      supporting_text: "phosphorylated eIF2α binds eIF2B in a way that blocks productive engagement of eIF2γ with the catalytic ε subunit, suppressing nucleotide exchange"
core_functions:
- molecular_function:
    id: GO:0005085
    label: guanyl-nucleotide exchange factor activity
  in_complex:
    id: GO:0005851
    label: eukaryotic translation initiation factor 2B complex
  directly_involved_in:
  - id: GO:0002183
    label: cytoplasmic translational initiation
  locations:
  - id: GO:0005829
    label: cytosol
  description: >-
    EIF2B4 (delta subunit) is part of the regulatory subcomplex of eIF2B, which
    catalyzes GDP-GTP exchange on eIF2. While the catalytic activity resides in
    the epsilon subunit, the delta subunit is essential for full GEF activity
    of the holoenzyme. PMID:11323413 demonstrates that "mammalian eIF2B can
    mediate release of eIF2-bound GDP" and PMID:15054402 shows that mutations
    in eIF2B subunits (including delta) cause 20-70% decrease in GEF activity.
  supported_by:
  - reference_id: PMID:11323413
    supporting_text: "mammalian eIF2B can mediate release of eIF2-bound GDP even in the absence of free nucleotide, indicating that it acts as a GDP dissociation stimulator protein"
  - reference_id: PMID:15054402
    supporting_text: "A significant decrease of 20-70% in GEF activity was observed in all mutated cells"
  - reference_id: file:human/EIF2B4/EIF2B4-deep-research-falcon.md
    supporting_text: "eIF2B's catalytic function is mainly attributed to the γ and ε subunits, while α/β/δ enhance full activity and provide regulatory control, including stress sensitivity"
- molecular_function:
    id: GO:0031369
    label: translation initiation factor binding
  in_complex:
    id: GO:0005851
    label: eukaryotic translation initiation factor 2B complex
  directly_involved_in:
  - id: GO:0006417
    label: regulation of translation
  locations:
  - id: GO:0005829
    label: cytosol
  description: >-
    EIF2B4/eIF2Bdelta forms a key interface for binding phosphorylated eIF2alpha
    during the integrated stress response. Phospho-eIF2alpha binds eIF2B at an
    interface that includes the alpha and delta subunits, blocking productive
    engagement of eIF2gamma with the catalytic epsilon subunit and thereby
    suppressing nucleotide exchange. This inhibitory interaction converts
    phospho-eIF2 into a competitive inhibitor of eIF2B, providing the molecular
    basis for ISR-mediated translational reprogramming.
  supported_by:
  - reference_id: PMID:29599213
    supporting_text: "eIF2 binds across the decameric interface, engaging the eIF2B alpha subunit, and beta and delta subunits from opposing tetramers"
  - reference_id: file:human/EIF2B4/EIF2B4-deep-research-falcon.md
    supporting_text: "phosphorylated eIF2α binds eIF2B in a way that blocks productive engagement of eIF2γ with the catalytic ε subunit, suppressing nucleotide exchange"
  - reference_id: PMID:36943285
    supporting_text: "Phosphorylation of eIF2α (p-eIF2α) blocks the eIF2B-directed exchange, consequently reducing the levels of eIF2•GTP"
- molecular_function:
    id: GO:0005085
    label: guanyl-nucleotide exchange factor activity
  in_complex:
    id: GO:0005851
    label: eukaryotic translation initiation factor 2B complex
  directly_involved_in:
  - id: GO:0006413
    label: translational initiation
  locations:
  - id: GO:0005829
    label: cytosol
  description: >-
    EIF2B4/eIF2Bdelta serves as a regulatory/scaffold subunit essential for assembly
    and stabilization of the decameric eIF2B holoenzyme that catalyzes GEF activity.
    The delta subunit, together with beta, forms the beta/delta core that supports
    higher-order assembly of eIF2B and is central to allosteric regulation by small
    molecules such as ISRIB. delta contributes to inter-subcomplex organization and
    proper stress-sensitive regulatory behavior of the holoenzyme; full GEF activity
    requires the assembled decamer.
  supported_by:
  - reference_id: PMID:24532666
    supporting_text: "is actually decameric, a dimer of eIF2B(βγδε) tetramers stabilized by 2 copies"
  - reference_id: file:human/EIF2B4/EIF2B4-deep-research-falcon.md
    supporting_text: "participates in assembly and stabilization of the full decameric eIF2B complex"
  - reference_id: file:human/EIF2B4/EIF2B4-deep-research-falcon.md
    supporting_text: "contributes to the β/δ \"core\" that supports higher-order assembly of eIF2B and is central to allosteric regulation by small molecules"
references:
- id: GO_REF:0000024
  title: Manual transfer of experimentally-verified manual GO annotation data to orthologs by curator judgment of sequence similarity.
  findings: []
- id: GO_REF:0000033
  title: Annotation inferences using phylogenetic trees
  findings: []
- id: GO_REF:0000043
  title: Gene Ontology annotation based on UniProtKB/Swiss-Prot keyword mapping
  findings: []
- id: GO_REF:0000044
  title: Gene Ontology annotation based on UniProtKB/Swiss-Prot Subcellular Location vocabulary mapping
  findings: []
- id: GO_REF:0000117
  title: Electronic Gene Ontology annotations created by ARBA machine learning models
  findings: []
- id: PMID:11323413
  title: Characterization of the mammalian initiation factor eIF2B complex as a GDP dissociation stimulator protein.
  findings:
  - statement: Demonstrated that eIF2B acts as a GDP dissociation stimulator protein
    supporting_text: "mammalian eIF2B can mediate release of eIF2-bound GDP even in the absence of free nucleotide, indicating that it acts as a GDP dissociation stimulator protein"
  - statement: Showed that all five subunits contribute to full activity
    supporting_text: "It is composed of five subunits, alpha-epsilon."
  - statement: Confirmed eIF2B mediates release of eIF2-bound GDP
    supporting_text: "Initiation factor eIF2B mediates a key regulatory step in the initiation of mRNA translation, i.e. the regeneration of active eIF2.GTP complexes."
- id: PMID:12499492
  title: A severe variant of childhood ataxia with central hypomyelination/vanishing white matter leukoencephalopathy related to EIF21B5 mutation.
  findings:
  - statement: Described severe VWM variant triggered by fever
    supporting_text: "A severe variant of childhood ataxia with central hypomyelination/vanishing white matter leukoencephalopathy"
- id: PMID:12556349
  title: Reduced amino acid availability inhibits muscle protein synthesis and decreases activity of initiation factor eIF2B.
  findings:
  - statement: Showed eIF2B activity is regulated by amino acid availability
    supporting_text: "Reduced amino acid availability inhibits muscle protein synthesis and decreases activity of initiation factor eIF2B"
- id: PMID:14566705
  title: 'eIF2B-related disorders: antenatal onset and involvement of multiple organs.'
  findings:
  - statement: Described severe prenatal forms of eIF2B-related disease
    supporting_text: "eIF2B-related disorders: antenatal onset and involvement of multiple organs"
  - statement: Showed multi-organ involvement
    supporting_text: "eIF2B-related disorders: antenatal onset and involvement of multiple organs"
- id: PMID:15054402
  title: Decreased guanine nucleotide exchange factor activity in eIF2B-mutated patients.
  findings:
  - statement: Measured 20-70% decrease in GEF activity in patient cells
    supporting_text: "A significant decrease of 20-70% in GEF activity was observed in all mutated cells"
  - statement: Correlated GEF activity decrease with disease severity
    supporting_text: "The severity of this decrement of GEF activity correlated with age at onset of the disease"
- id: PMID:15060152
  title: Mutations linked to leukoencephalopathy with vanishing white matter impair the function of the eukaryotic initiation factor 2B complex in diverse ways.
  findings:
  - statement: Characterized functional effects of VWM mutations on eIF2B
    supporting_text: "Mutations linked to leukoencephalopathy with vanishing white matter impair the function of the eukaryotic initiation factor 2B complex in diverse ways"
- id: PMID:15217090
  title: The life and death of oligodendrocytes in vanishing white matter disease.
  findings:
  - statement: Documented oligodendrocyte pathology in VWM
    supporting_text: "Vanishing white matter disease (VWM) is a progressive cavitating disease of central white matter due to a deficiency of the translation initiation factor eIF2B"
  - statement: Showed both apoptosis and proliferation of oligodendrocytes
    supporting_text: "Oligodendrocytes appear to be numerically increased in some white matter areas, while decreased in others"
- id: PMID:15507143
  title: Screening for known mutations in EIF2B genes in a large panel of patients with premature ovarian failure.
  findings:
  - statement: Linked EIF2B mutations to premature ovarian failure
    supporting_text: "Screening for known mutations in EIF2B genes in a large panel of patients with premature ovarian failure"
- id: PMID:16289705
  title: An efficient mammalian cell-free translation system supplemented with translation factors.
  findings:
  - statement: Demonstrated eIF2B augments translation in cell-free systems
  - statement: Showed eIF2 and eIF2B enhance mRNA translation
- id: PMID:25416956
  title: A proteome-scale map of the human interactome network.
  findings:
  - statement: High-throughput interactome mapping
- id: PMID:25858979
  title: Stress responses. Mutations in a translation initiation factor identify the target of a memory-enhancing compound.
  findings:
  - statement: Identified eIF2B as the target of ISRIB
  - statement: Showed mutations in delta subunit affect ISRIB response
  - statement: Demonstrated ISRIB stimulates eIF2B GEF activity
- id: PMID:25910212
  title: Widespread macromolecular interaction perturbations in human genetic disorders.
  findings:
  - statement: Protein interaction study
- id: PMID:27023709
  title: Expression, purification, and crystallization of Schizosaccharomyces pombe eIF2B.
  findings:
  - statement: Structural characterization of eIF2B
- id: PMID:28169297
  title: Comparative influenza protein interactomes identify the role of plakophilin 2 in virus restriction.
  findings:
  - statement: Identified viral protein interactions with eIF2B subunits
- id: PMID:29599213
  title: Structure of the nucleotide exchange factor eIF2B reveals mechanism of memory-enhancing molecule.
  findings:
  - statement: Solved atomic structure of human eIF2B with ISRIB
  - statement: Showed decameric assembly is required for full activity
  - statement: Demonstrated ISRIB stabilizes decameric form
- id: PMID:29599245
  title: Binding of ISRIB reveals a regulatory site in the nucleotide exchange factor eIF2B.
  findings:
  - statement: Characterized ISRIB binding site on eIF2B
- id: PMID:31515488
  title: Extensive disruption of protein interactions by genetic variants across the allele frequency spectrum in human populations.
  findings:
  - statement: Protein interaction study
- id: PMID:32296183
  title: A reference map of the human binary protein interactome.
  findings:
  - statement: Binary interactome mapping
- id: PMID:32814053
  title: Interactome Mapping Provides a Network of Neurodegenerative Disease Proteins and Uncovers Widespread Protein Aggregation in Affected Brains.
  findings:
  - statement: Neurodegenerative disease interactome
- id: PMID:33961781
  title: Dual proteome-scale networks reveal cell-specific remodeling of the human interactome.
  findings:
  - statement: Cell-specific interactome study
- id: PMID:8626696
  title: T-cell activation leads to rapid stimulation of translation initiation factor eIF2B and inactivation of glycogen synthase kinase-3.
  findings:
  - statement: Showed eIF2B is rapidly activated after T-cell stimulation
  - statement: Linked GSK-3 inactivation to eIF2B activation
- id: Reactome:R-HSA-72670
  title: Formation of eIF2:GDP:eIF2B intermediate
  findings:
  - statement: Pathway annotation for eIF2B function
- id: Reactome:R-HSA-72722
  title: eIF2 activation
  findings:
  - statement: Pathway annotation for eIF2 activation by eIF2B
- id: file:human/EIF2B4/EIF2B4-deep-research-openai.md
  title: Deep research on EIF2B4 function
  findings:
  - statement: Comprehensive review of eIF2B structure and function
  - statement: Documented role in integrated stress response
  - statement: Described subcellular localization to cytosol and eIF2B bodies
- id: file:human/EIF2B4/EIF2B4-deep-research-falcon.md
  title: Falcon deep research on EIF2B4 function
  findings:
  - statement: EIF2B4/eIF2Bdelta is a regulatory/scaffold subunit (not catalytic) that supports decameric holoenzyme assembly and contributes to the beta/delta core central to allosteric regulation
    supporting_text: "eIF2B's catalytic function is mainly attributed to the γ and ε subunits, while α/β/δ enhance full activity and provide regulatory control, including stress sensitivity"
  - statement: Phospho-eIF2alpha binds an interface that includes EIF2B4 (delta) and blocks engagement of eIF2gamma with the catalytic epsilon subunit
    supporting_text: "phosphorylated eIF2α binds eIF2B in a way that blocks productive engagement of eIF2γ with the catalytic ε subunit, suppressing nucleotide exchange"
  - statement: eIF2B localizes to discrete cytoplasmic eIF2B bodies with cell-type-specific composition
    supporting_text: "eIF2B localizes to discrete cytoplasmic foci called eIF2B bodies, which are interpreted as sites of eIF2B GEF activity and exhibit cell-type-specific composition in neuronal and glial cell lines"
- id: PMID:24532666
  title: Analysis of the subunit organization of the eIF2B complex reveals new insights into its structure and regulation.
  findings:
  - statement: Established eIF2B as heterodecamer that is a dimer of tetramers stabilized by additional subunits
    supporting_text: "is actually decameric, a dimer of eIF2B(βγδε) tetramers stabilized by 2 copies"
- id: PMID:36943285
  title: 'Surviving and Adapting to Stress: Translational Control and the Integrated Stress Response.'
  findings:
  - statement: Authoritative ISR review documenting that eIF2alpha phosphorylation inhibits eIF2B GEF activity
    supporting_text: "Phosphorylation of eIF2α (p-eIF2α) blocks the eIF2B-directed exchange, consequently reducing the levels of eIF2•GTP that are required for delivery of methionyl initiator tRNA"
- id: PMID:37014850
  title: eIF2Bdelta blocks the integrated stress response and maintains eIF2B activity and cancer metastasis by overexpression in breast cancer stem cells.
  findings:
  - statement: Elevated eIF2Bdelta supports cancer stem cell metastasis through ISR suppression
- id: PMID:39139316
  title: 'Ovarioleukodystrophy Due to EIF2B Genes: Systematic Review and Case Report.'
  findings:
  - statement: Systematic review of 20 worldwide ovarioleukodystrophy cases highlighting EIF2B4 involvement
    supporting_text: "This resulted in a series of 20 cases of women with ovarioleukodystrophy due to variants in the EIF2B gene complex. The median age of onset was 19 years (range 0.6-40)"
  - statement: Reported new case with homozygous EIF2B4 c.725C>T (p.Pro242Leu)
    supporting_text: "identified the variant c.725C>T (NM_015636.3; p.Pro242Leu) in the EIF2B4 gene in a homozygous state"
- id: PMID:39310746
  title: eIF2B localization and its regulation during the integrated stress response is cell-type specific.
  findings:
  - statement: eIF2B localization during the ISR is cell-type specific
    supporting_text: "eIF2B localization and its regulation during the integrated stress response is cell-type specific"
- id: PMID:37981684
  title: Genotypic and phenotypic heterogeneity among Chinese pediatric genetic white matter disorders.
  findings:
  - statement: Pediatric cohort identifying EIF2B4 in patients with white matter disorders
status: COMPLETE