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.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0002183 cytoplasmic translational initiation | IBA GO_REF:0000033 | ACCEPT | 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]. 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." Supporting Evidence: PMID:11323413 Initiation factor eIF2B mediates a key regulatory step in the initiation of mRNA translation, i.e. the regeneration of active eIF2.GTP complexes. file:human/EIF2B4/EIF2B4-deep-research-openai.md eIF2B serves as the sole guanine nucleotide exchange factor (GEF) for eIF2, playing a pivotal role in recycling eIF2 for continued protein synthesis |
| GO:0005851 eukaryotic translation initiation factor 2B complex | IBA GO_REF:0000033 | ACCEPT | 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]. 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." Supporting Evidence: PMID:29599213 Formation of fully active, decameric eIF2B holoenzyme depended on the assembly of two identical tetrameric subcomplexes PMID:11323413 It is composed of five subunits, alpha-epsilon. PMID:24532666 Analysis of the subunit organization of the eIF2B complex reveals new insights into its structure and regulation file:human/EIF2B4/EIF2B4-deep-research-falcon.md eIF2B is a decamer composed of two copies of each of five subunits (Ξ±βΞ΅) and place Ξ΄ (EIF2B4) among the regulatory subunits (Ξ±/Ξ²/Ξ΄) rather than the catalytic subunits (Ξ³/Ξ΅) |
| GO:0003743 translation initiation factor activity | IEA GO_REF:0000043 | ACCEPT | 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]. 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. Supporting Evidence: PMID:16289705 eIF2 (eukaryotic translation initiation factor 2) and eIF2B augmented translation of capped, uncapped and encephalomyocarditis virus-internal ribosome entry site-promoted mRNAs. |
| GO:0005085 guanyl-nucleotide exchange factor activity | IEA GO_REF:0000117 | ACCEPT | 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. 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. Supporting Evidence: PMID:11323413 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 file:human/EIF2B4/EIF2B4-deep-research-falcon.md eIF2B is the GEF for eIF2, recycling inactive eIF2βGDP to active eIF2βGTP, thereby replenishing the pool of eIF2 needed to form the ternary complex (eIF2βGTPΒ·Met-tRNAi) and initiate translation |
| GO:0005829 cytosol | IEA GO_REF:0000044 | ACCEPT | 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). 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. Supporting Evidence: file:human/EIF2B4/EIF2B4-deep-research-openai.md The EIF2B4 gene product (eIF2Bdelta) carries out its function in the cytosol, where translation initiation occurs. PMID:39310746 eIF2B localization and its regulation during the integrated stress response is cell-type specific |
| GO:0005851 eukaryotic translation initiation factor 2B complex | IEA GO_REF:0000117 | ACCEPT | Summary: Duplicate annotation (different evidence source from IBA above) confirming EIF2B4 as a component of the eIF2B complex. Reason: This IEA annotation reinforces that EIF2B4 is part of the eIF2B complex. Multiple evidence lines supporting the same conclusion is appropriate. Supporting Evidence: PMID:29599213 Formation of fully active, decameric eIF2B holoenzyme depended on the assembly of two identical tetrameric subcomplexes |
| GO:0006412 translation | IEA GO_REF:0000043 | ACCEPT | 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. 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. Supporting Evidence: PMID:16289705 eIF2 (eukaryotic translation initiation factor 2) and eIF2B augmented translation of capped, uncapped and encephalomyocarditis virus-internal ribosome entry site-promoted mRNAs. |
| GO:0006413 translational initiation | IEA GO_REF:0000043 | ACCEPT | Summary: EIF2B4 is involved in translational initiation as part of the eIF2B complex, which regenerates eIF2-GTP needed for initiating translation of mRNAs. 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." Supporting Evidence: PMID:11323413 Initiation factor eIF2B mediates a key regulatory step in the initiation of mRNA translation, i.e. the regeneration of active eIF2.GTP complexes. |
| GO:0007417 central nervous system development | IEA GO_REF:0000117 | KEEP AS NON CORE | 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. 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. Supporting Evidence: PMID:15217090 Vanishing white matter disease (VWM) is a progressive cavitating disease of central white matter due to a deficiency of the translation initiation factor eIF2B. |
| GO:0048513 animal organ development | IEA GO_REF:0000117 | REMOVE | 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. 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. Supporting Evidence: file:human/EIF2B4/EIF2B4-deep-research-openai.md eIF2B serves as the sole guanine nucleotide exchange factor (GEF) for eIF2, playing a pivotal role in recycling eIF2 for continued protein synthesis |
| GO:0005515 protein binding | IPI PMID:25416956 A proteome-scale map of the human interactome network. | REMOVE | Summary: Generic protein binding annotation from high-throughput interactome mapping. EIF2B4 binds to EIF2B2 as part of the eIF2B complex. 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. Supporting Evidence: PMID:25416956 A proteome-scale map of the human interactome network |
| GO:0005515 protein binding | IPI PMID:25910212 Widespread macromolecular interaction perturbations in human... | REMOVE | Summary: High-throughput interaction study showing EIF2B4 interacts with EIF2B2. 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. Supporting Evidence: PMID:25910212 Widespread macromolecular interaction perturbations in human genetic disorders |
| GO:0005515 protein binding | IPI PMID:28169297 Comparative influenza protein interactomes identify the role... | REMOVE | 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. 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. Supporting Evidence: PMID:28169297 Comparative influenza protein interactomes identify the role of plakophilin 2 in virus restriction |
| GO:0005515 protein binding | IPI PMID:29599245 Binding of ISRIB reveals a regulatory site in the nucleotide... | REMOVE | Summary: Study examining binding of ISRIB to eIF2B complex including EIF2B4. 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." Supporting Evidence: PMID:29599245 Binding of ISRIB reveals a regulatory site in the nucleotide exchange factor eIF2B |
| GO:0005515 protein binding | IPI PMID:31515488 Extensive disruption of protein interactions by genetic vari... | REMOVE | Summary: High-throughput study on protein-protein interactions across human populations. Reason: Generic protein binding annotation from high-throughput study is not informative. More specific molecular function terms are available. Supporting Evidence: PMID:31515488 Extensive disruption of protein interactions by genetic variants across the allele frequency spectrum in human populations |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | REMOVE | Summary: Human binary interactome mapping study. 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. Supporting Evidence: PMID:32296183 A reference map of the human binary protein interactome |
| GO:0005515 protein binding | IPI PMID:32814053 Interactome Mapping Provides a Network of Neurodegenerative ... | REMOVE | Summary: Study on interactome mapping in neurodegenerative disease. 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. Supporting Evidence: PMID:32814053 Interactome Mapping Provides a Network of Neurodegenerative Disease Proteins and Uncovers Widespread Protein Aggregation in Affected Brains |
| GO:0005515 protein binding | IPI PMID:33961781 Dual proteome-scale networks reveal cell-specific remodeling... | REMOVE | Summary: Dual proteome-scale network study on cell-specific interactomes. Reason: Generic protein binding is uninformative. Better molecular function terms exist. Supporting Evidence: PMID:33961781 Dual proteome-scale networks reveal cell-specific remodeling of the human interactome |
| GO:0005851 eukaryotic translation initiation factor 2B complex | IPI PMID:29599213 Structure of the nucleotide exchange factor eIF2B reveals me... | ACCEPT | 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. 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." Supporting Evidence: PMID:29599213 we solved an atomic-resolution structure of ISRIB bound in a deep cleft within decameric human eIF2B by cryo-electron microscopy |
| GO:0045948 positive regulation of translational initiation | IDA PMID:29599213 Structure of the nucleotide exchange factor eIF2B reveals me... | ACCEPT | Summary: The eIF2B complex positively regulates translation initiation by catalyzing GDP-GTP exchange on eIF2, thereby regenerating active eIF2-GTP complexes. 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. Supporting Evidence: PMID:29599213 Formation of fully active, decameric eIF2B holoenzyme depended on the assembly of two identical tetrameric subcomplexes file:human/EIF2B4/EIF2B4-deep-research-openai.md By recycling eIF2-GDP to eIF2-GTP, eIF2B enables continuous rounds of translation initiation |
| GO:0002183 cytoplasmic translational initiation | IDA PMID:27023709 Expression, purification, and crystallization of Schizosacch... | ACCEPT | Summary: Study on expression and crystallization of S. pombe eIF2B, providing functional evidence for the role of eIF2B subunits in cytoplasmic translation initiation. Reason: EIF2B4 is part of the eIF2B complex essential for cytoplasmic translation initiation. The IDA evidence from this study supports the annotation. Supporting Evidence: PMID:27023709 Expression, purification, and crystallization of Schizosaccharomyces pombe eIF2B |
| GO:0005085 guanyl-nucleotide exchange factor activity | IDA PMID:25858979 Stress responses. Mutations in a translation initiation fact... | ACCEPT | 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. 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. Supporting Evidence: PMID:25858979 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 |
| GO:0005085 guanyl-nucleotide exchange factor activity | IDA PMID:27023709 Expression, purification, and crystallization of Schizosacch... | ACCEPT | Summary: Study providing functional evidence for eIF2B GEF activity through structural and biochemical characterization. Reason: Multiple lines of evidence confirm eIF2B's GEF activity. This annotation is consistent with the well-established function of the eIF2B complex. Supporting Evidence: PMID:27023709 Expression, purification, and crystallization of Schizosaccharomyces pombe eIF2B |
| GO:0005851 eukaryotic translation initiation factor 2B complex | IDA PMID:27023709 Expression, purification, and crystallization of Schizosacch... | ACCEPT | Summary: Direct evidence for EIF2B4 as a component of the eIF2B complex from crystallization studies. Reason: Strong experimental evidence from structural studies confirming the delta subunit's membership in the eIF2B complex. Supporting Evidence: PMID:27023709 Expression, purification, and crystallization of Schizosaccharomyces pombe eIF2B |
| GO:0050852 T cell receptor signaling pathway | IDA PMID:8626696 T-cell activation leads to rapid stimulation of translation ... | KEEP AS NON CORE | 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. 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. Supporting Evidence: PMID:8626696 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 |
| GO:0005829 cytosol | TAS Reactome:R-HSA-72670 | ACCEPT | Summary: Reactome pathway annotation for formation of eIF2:GDP:eIF2B intermediate, which occurs in the cytosol. Reason: The cytosolic localization is consistent with the function in translation initiation, which occurs in the cytoplasm. Supporting Evidence: Reactome:R-HSA-72670 Formation of eIF2:GDP:eIF2B intermediate |
| GO:0005829 cytosol | TAS Reactome:R-HSA-72722 | ACCEPT | Summary: Reactome pathway annotation for eIF2 activation, which occurs in the cytosol. Reason: Consistent with cytosolic localization for translation initiation function. Supporting Evidence: file:human/EIF2B4/EIF2B4-deep-research-openai.md The EIF2B4 gene product (eIF2Bdelta) carries out its function in the cytosol, where translation initiation occurs. |
| GO:0031369 translation initiation factor binding | ISS GO_REF:0000024 | ACCEPT | 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. 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. Supporting Evidence: PMID:29599213 eIF2 binds across the decameric interface, engaging the eIF2B alpha subunit, and beta and delta subunits from opposing tetramers |
| GO:0006413 translational initiation | IDA PMID:16289705 An efficient mammalian cell-free translation system suppleme... | ACCEPT | Summary: Study demonstrating that supplementation with eIF2B enhances translation in mammalian cell-free systems. 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." Supporting Evidence: PMID:16289705 eIF2 (eukaryotic translation initiation factor 2) and eIF2B augmented translation of capped, uncapped and encephalomyocarditis virus-internal ribosome entry site-promoted mRNAs. |
| GO:0009408 response to heat | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: EIF2B is regulated as part of the integrated stress response, which includes heat stress. Inferred from sequence similarity to rat ortholog. 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." Supporting Evidence: file:human/EIF2B4/EIF2B4-deep-research-openai.md 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 |
| GO:0009408 response to heat | TAS PMID:12499492 A severe variant of childhood ataxia with central hypomyelin... | KEEP AS NON CORE | Summary: Study describing vanishing white matter disease related to EIF2B5 mutation, noting that fever (heat stress) triggers neurological deterioration. 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. Supporting Evidence: PMID:12499492 A severe variant of childhood ataxia with central hypomyelination/vanishing white matter leukoencephalopathy related to EIF21B5 mutation |
| GO:0014003 oligodendrocyte development | IMP PMID:15217090 The life and death of oligodendrocytes in vanishing white ma... | KEEP AS NON CORE | 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. 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." Supporting Evidence: PMID:15217090 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. |
| GO:0003743 translation initiation factor activity | IDA PMID:16289705 An efficient mammalian cell-free translation system suppleme... | ACCEPT | 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. 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. Supporting Evidence: PMID:16289705 eIF2 (eukaryotic translation initiation factor 2) and eIF2B augmented translation of capped, uncapped and encephalomyocarditis virus-internal ribosome entry site-promoted mRNAs. |
| GO:0009749 response to glucose | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: eIF2B activity is regulated by metabolic signals including glucose levels, through insulin signaling and GSK-3 phosphorylation of eIF2Bepsilon. 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. Supporting Evidence: file:human/EIF2B4/EIF2B4-deep-research-openai.md insulin - through the PI3K/Akt pathway - activates eIF2B by inhibiting GSK-3 kinase |
| GO:0043434 response to peptide hormone | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: eIF2B activity is modulated by insulin (a peptide hormone) through the GSK-3 pathway. Inferred from sequence similarity to rat ortholog. 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. Supporting Evidence: PMID:8626696 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. |
| GO:0005515 protein binding | IPI PMID:15060152 Mutations linked to leukoencephalopathy with vanishing white... | REMOVE | Summary: Study examining mutations linked to vanishing white matter disease and their effects on eIF2B complex function and interactions with EIF2B2. 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. Supporting Evidence: PMID:15060152 Mutations linked to leukoencephalopathy with vanishing white matter impair the function of the eukaryotic initiation factor 2B complex in diverse ways |
| GO:0001541 ovarian follicle development | IMP PMID:15507143 Screening for known mutations in EIF2B genes in a large pane... | KEEP AS NON CORE | Summary: Study screening for EIF2B mutations in patients with premature ovarian failure. Some EIF2B4 mutations cause ovarioleukodystrophy. 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. Supporting Evidence: PMID:15507143 Screening for known mutations in EIF2B genes in a large panel of patients with premature ovarian failure PMID:39139316 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%) |
| GO:0005085 guanyl-nucleotide exchange factor activity | IDA PMID:11323413 Characterization of the mammalian initiation factor eIF2B co... | ACCEPT | Summary: Seminal study characterizing mammalian eIF2B as a GDP dissociation stimulator protein. Demonstrated that eIF2B can mediate release of eIF2-bound GDP. 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. Supporting Evidence: PMID:11323413 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 file:human/EIF2B4/EIF2B4-deep-research-falcon.md eIF2B's catalytic function is mainly attributed to the Ξ³ and Ξ΅ subunits, while Ξ±/Ξ²/Ξ΄ enhance full activity and provide regulatory control, including stress sensitivity |
| GO:0005737 cytoplasm | IDA PMID:11323413 Characterization of the mammalian initiation factor eIF2B co... | ACCEPT | Summary: Study demonstrating eIF2B function in the cytoplasm through biochemical characterization of the complex. Reason: The cytoplasmic localization is well-established and consistent with the function in translation initiation, which occurs in the cytoplasm. Supporting Evidence: PMID:11323413 Characterization of the mammalian initiation factor eIF2B complex as a GDP dissociation stimulator protein |
| GO:0005851 eukaryotic translation initiation factor 2B complex | IDA PMID:11323413 Characterization of the mammalian initiation factor eIF2B co... | ACCEPT | Summary: Study characterizing the five-subunit eIF2B complex, confirming EIF2B4 (delta) as a component. Reason: Direct experimental evidence. The study states "It is composed of five subunits, alpha-epsilon." Supporting Evidence: PMID:11323413 It is composed of five subunits, alpha-epsilon. PMID:24532666 is actually decameric, a dimer of eIF2B(βγδΡ) tetramers stabilized by 2 copies |
| GO:0042552 myelination | IMP PMID:14566705 eIF2B-related disorders: antenatal onset and involvement of ... | KEEP AS NON CORE | Summary: Study on eIF2B-related disorders showing that mutations cause myelination defects. Vanishing white matter disease involves loss of myelin. 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. Supporting Evidence: PMID:14566705 eIF2B-related disorders: antenatal onset and involvement of multiple organs |
| GO:0005085 guanyl-nucleotide exchange factor activity | IMP PMID:15054402 Decreased guanine nucleotide exchange factor activity in eIF... | ACCEPT | Summary: Study measuring GEF activity in cells from patients with eIF2B mutations. Demonstrated 20-70% decrease in GEF activity in mutated cells. 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. Supporting Evidence: PMID:15054402 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. |
| GO:0005851 eukaryotic translation initiation factor 2B complex | IDA PMID:15060152 Mutations linked to leukoencephalopathy with vanishing white... | ACCEPT | Summary: Study on mutations affecting eIF2B complex function, confirming EIF2B4 as a component of the complex. Reason: Direct experimental evidence from studies of the eIF2B complex. Supporting Evidence: PMID:15060152 Mutations linked to leukoencephalopathy with vanishing white matter impair the function of the eukaryotic initiation factor 2B complex in diverse ways |
| GO:0006417 regulation of translation | NAS PMID:12556349 Reduced amino acid availability inhibits muscle protein synt... | ACCEPT | Summary: Study showing that reduced amino acid availability inhibits muscle protein synthesis and decreases eIF2B activity. 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." Supporting Evidence: PMID:12556349 Reduced amino acid availability inhibits muscle protein synthesis and decreases activity of initiation factor eIF2B PMID:36943285 Phosphorylation of eIF2Ξ± (p-eIF2Ξ±) blocks the eIF2B-directed exchange, consequently reducing the levels of eIF2β’GTP that are required for delivery of methionyl initiator tRNA file:human/EIF2B4/EIF2B4-deep-research-falcon.md phosphorylated eIF2Ξ± binds eIF2B in a way that blocks productive engagement of eIF2Ξ³ with the catalytic Ξ΅ subunit, suppressing nucleotide exchange |
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