EIF2B4 encodes the delta subunit of eukaryotic translation initiation factor 2B, the cytosolic complex that promotes GDP release from eIF2 and regenerates active eIF2 for translation initiation. Delta forms part of the regulatory assembly with the alpha and beta subunits and contributes to complex organization and regulation by phosphorylated eIF2 and the small molecule ISRIB. The epsilon subunit contains the principal catalytic exchange activity. Human delta variants can impair whole-complex exchange and cause vanishing white matter disease, sometimes accompanied by ovarian dysfunction. Three natural delta protein products are recorded, but their assembly and regulatory properties have not all been directly compared.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0002183 cytoplasmic translational initiation | IBA GO_REF:0000033 | ACCEPT | Summary: Conserved participation in cytoplasmic translation initiation. Reason: The literal PAINT IBD for GO:0002183 occurs at PTN000027922 on the 20-node path to human Q9UI10. The complete 523-residue target sequence matches the saved alignment, and the inherited source set includes direct target evidence as expected. No loss annotation occurs on this saved path. Human reconstitution and the human comparator in PMID:27023709 independently support participation of the delta-containing complex in cytoplasmic translation initiation; the principal structural work in that paper is S. pombe. 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 file:human/EIF2B4/EIF2B4-source-guide.md file:human/EIF2B4/EIF2B4-bioinformatics/RESULTS.md |
| GO:0005851 eukaryotic translation initiation factor 2B complex | IBA GO_REF:0000033 | ACCEPT | Summary: Conserved eIF2B complex membership. Reason: The GO:0005851 IBD and its complete literal source set are present at PTN000027922 on the target ancestry path. Target self-evidence is legitimate experimental grounding, not circular propagation. The human delta subunit is a structural constituent of eIF2B in reconstitution and cryo-EM studies. The PAINT reconstruction supports inheritance of this complex membership without asserting identical functions for all natural isoforms. 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. 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΅) file:human/EIF2B4/EIF2B4-source-guide.md file:human/EIF2B4/EIF2B4-bioinformatics/RESULTS.md |
| GO:0003743 translation initiation factor activity | IEA GO_REF:0000043 | ACCEPT | Summary: Translation initiation factor activity is retained. Reason: The historical keyword-derived assertion describes the delta subunit as part of the translation initiation machinery. Human native-factor purification, human-complex reconstitution and subunit assembly studies support this role. The term does not require assigning the entire nucleotide-exchange chemistry to delta. This source key is absent from the complete current GOA snapshot. Its retired flag records that source-lifecycle change while preserving this positive biological assessment and the original source identity. 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. file:human/EIF2B4/EIF2B4-source-guide.md |
| GO:0005085 guanyl-nucleotide exchange factor activity | IEA GO_REF:0000117 | ACCEPT | Summary: GEF participation is supported; the electronic relation needs checking. Reason: The literal ARBA00028188 rule assigns GO:0005085 through the target FunFam 3.40.50.10470:FF:000002. Its saved conclusion supplies the GO term but does not expose a qualifier or a trace to a particular experimental relation. Delta contributes structure, assembly and regulation to the exchange-active eIF2B complex; human delta-interface mutants affect assembly and whole-complex activity. The imported enables relation is preserved, with a conditional curator query about contributes_to rather than a claim that delta must be active in isolation. 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 file:human/EIF2B4/EIF2B4-source-guide.md file:human/EIF2B4/EIF2B4-bioinformatics/RESULTS.md |
| GO:0005829 cytosol | IEA GO_REF:0000044 | ACCEPT | Summary: Cytosolic localization is supported. Reason: The source maps UniProt SL-0091 to cytosol. Independent native human cytoplasmic purification and target-resolved Reactome membership support this localization. PMID:39310746 also examines endogenous delta immunolocalization in human neural and glial cell lines, with cell-dependent recruitment to cytoplasmic eIF2B bodies. Those context-dependent bodies do not negate a cytosolic pool. 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. file:human/EIF2B4/EIF2B4-source-guide.md file:human/EIF2B4/EIF2B4-bioinformatics/RESULTS.md |
| GO:0005851 eukaryotic translation initiation factor 2B complex | IEA GO_REF:0000117 | ACCEPT | Summary: The electronic eIF2B complex assignment is well supported. Reason: ARBA00088579 contains the matching target FunFam and Chordata conditions for GO:0005851. Human delta is directly present in reconstituted and endogenous eIF2B assemblies. The electronic rule is corroborated by those primary studies; no independent catalytic activity or universal natural-product equivalence is inferred. Supporting Evidence: PMID:29599213 Formation of fully active, decameric eIF2B holoenzyme depended on the assembly of two identical tetrameric subcomplexes file:human/EIF2B4/EIF2B4-source-guide.md file:human/EIF2B4/EIF2B4-bioinformatics/RESULTS.md |
| GO:0006412 translation | IEA GO_REF:0000043 | MODIFY | Summary: Specify cytoplasmic translation initiation. Reason: The historical protein-biosynthesis keyword supports a real translational role, but the established activity of delta-containing eIF2B is in cytoplasmic initiation through reactivation of eIF2. GO:0002183 states that role more precisely than translation. This is a term refinement, not a biological rejection or an automatic retirement of the historical source key. Proposed replacements: cytoplasmic translational initiation 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. file:human/EIF2B4/EIF2B4-source-guide.md |
| GO:0006413 translational initiation | IEA GO_REF:0000043 | MODIFY | Summary: Specify cytoplasmic translation initiation. Reason: The historical initiation keyword is biologically correct. Human eIF2B reconstitution and the human cell-free comparator identify the cytoplasmic initiation process more precisely, supporting GO:0002183. The source dictionary and its absent-current lifecycle status remain separate from this scientific refinement. Proposed replacements: cytoplasmic translational initiation 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-source-guide.md |
| GO:0007417 central nervous system development | IEA GO_REF:0000117 | MARK AS OVER ANNOTATED | Summary: Clinical CNS abnormalities do not establish the specific developmental participation inferred by this rule. Reason: ARBA00026561 assigns GO:0007417 through a condition matching the actual EIF2B4 delta FunFam, 3.40.50.10470:FF:000002. Human biallelic EIF2B4 cases in PMID:14566705 have genuine brain and multisystem abnormalities; those observations are preserved. GO:0007417 describes progression of the central nervous system from formation to maturity. The inspected clinical evidence and family match do not identify a CNS-development step performed by EIF2B4 beyond its established contribution to translation. Mark this electronic process assignment as over-annotated: disease consequences of impaired translation do not by themselves establish the more specific developmental participation. This does not assert that EIF2B4 lacks all developmental roles or invalidate the separate experimental myelination annotation. Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: CONTEXT OR TISSUE MISMATCH ROLE CONFLATION Sources checked: ARBA:ARBA00026561 Β· ARBA00026561 SOURCE WEAK OR INFERRED The saved rule condition set 55 (zero-based) matches Q9UI10 FunFam 3.40.50.10470:FF:000002 and emits the imported term. The family match is valid; it does not establish a step in CNS development. Clinical consequences of impaired translation are not sufficient evidence for that process role. The rule training examples and their original mechanistic provenance were not reconstructed. 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. file:human/EIF2B4/EIF2B4-source-guide.md |
| GO:0048513 animal organ development | IEA GO_REF:0000117 | MARK AS OVER ANNOTATED | Summary: Multisystem disease establishes developmental consequences, not a defined organ-development role. Reason: ARBA00029247 has a target-matching delta FunFam condition and assigns GO:0048513. The inspected PMID:14566705 clinical table genuinely identifies EIF2B4 patients with brain/kidney abnormalities and an A391D patient with lens, pancreas and ovarian abnormalities. These positive developmental phenotypes are retained. However, the term describes the progression of organs from formation to mature structure; the evidence here does not identify an organ-development step performed by EIF2B4 beyond its general contribution to translation. Mark this electronic process assignment as over-annotated rather than treating multisystem disease consequences as sufficient process participation. This does not deny the human phenotypes or establish that EIF2B4 has no developmental role. Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: CONTEXT OR TISSUE MISMATCH ROLE CONFLATION Sources checked: ARBA:ARBA00029247 Β· ARBA00029247 SOURCE WEAK OR INFERRED The saved rule condition set 240 (zero-based) matches Q9UI10 FunFam 3.40.50.10470:FF:000002 and emits the imported term. The family match is valid; it does not establish a step in animal organ development. Clinical consequences of impaired translation are not sufficient evidence for that process role. The rule training examples and their original mechanistic provenance were not reconstructed. 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 file:human/EIF2B4/EIF2B4-source-guide.md |
| GO:0005515 protein binding | IPI PMID:25416956 A proteome-scale map of the human interactome network. | MODIFY | Summary: Refine the positive beta-subunit association to factor binding. Reason: Literal IntAct records for PMID:25416956 join Q9UI10 to human Q53XC2 in yeast two-hybrid screening and retesting. The official Q53XC2 sequence is identical to the reviewed 351-residue EIF2B2 P49770 sequence. Beta is an independently established translation initiation factor subunit, so GO:0031369 is warranted. Curated reference checksums and variant features are preserved separately; they do not prove that every tested insert was full length or that a native cellular interface was assayed. Proposed replacements: translation initiation factor binding Supporting Evidence: file:human/EIF2B4/EIF2B4-source-guide.md file:human/EIF2B4/EIF2B4-bioinformatics/RESULTS.md |
| GO:0005515 protein binding | IPI PMID:25910212 Widespread macromolecular interaction perturbations in human... | MODIFY | Summary: Refine the beta-subunit interaction to factor binding. Reason: The source-specific IntAct records identify human EIF2B2 P49770 and EIF2B4 in array, pooling and validated two-hybrid assays, including separately annotated mutation effects. The positive wild-type association and beta partner class justify GO:0031369. The paper abstract and literal assay records were examined; no claim is made that this particular pair received every orthogonal validation used elsewhere in the study. Proposed replacements: translation initiation factor binding Supporting Evidence: file:human/EIF2B4/EIF2B4-source-guide.md file:human/EIF2B4/EIF2B4-bioinformatics/RESULTS.md |
| GO:0005515 protein binding | IPI PMID:28169297 Comparative influenza protein interactomes identify the role... | KEEP AS NON CORE | Summary: Retain the viral M2 association without a transporter-binding refinement. Reason: The literal records identify influenza A/Puerto Rico/8/1934 M2 P06821 with human EIF2B4 in anti-tag coimmunoprecipitation and AP-MS association assays in HEK293 cells, including an infected-cell context. The co-IP record locates Supplementary Figure 6b; the source Methods describe tagged viral proteins and quantitative controls, but supplementary blot pixels and an exact EIF2B4 insert sequence were not independently inspected. M2 is a proton channel, but GO:0044325 requires binding to that transporter. Co-complex recovery does not resolve whether EIF2B4 contacts M2 or an intervening component, so the class assignment alone does not establish this specific binding activity. Retain the supported generic association as non-core; neither an artefact nor a direct channel-regulatory function is inferred. Supporting Evidence: file:human/EIF2B4/EIF2B4-source-guide.md file:human/EIF2B4/EIF2B4-bioinformatics/RESULTS.md |
| GO:0005515 protein binding | IPI PMID:29599245 Binding of ISRIB reveals a regulatory site in the nucleotide... | MODIFY | Summary: Retain the distinct ISRIB structural paper and refine factor binding. Reason: PMID:29599245 is a valid paper distinct from PMID:29599213. Its recovered main text and captions describe endogenous human HeLa eIF2B and a beta/delta regulatory interface, with the ISRIB pocket and separate hamster mutant binding studies. Those positive human structural associations support translation initiation factor binding. This inherited aggregate source has no WITH partner and is absent from current GOA; neither fact licenses replacing its identifier or erasing it. No coordinate-level contact reconstruction or supplementary Methods read is claimed. Proposed replacements: translation initiation factor binding Supporting Evidence: file:human/EIF2B4/EIF2B4-source-guide.md file:human/EIF2B4/EIF2B4-bioinformatics/RESULTS.md |
| GO:0005515 protein binding | IPI PMID:31515488 Extensive disruption of protein interactions by genetic vari... | MODIFY | Summary: Refine the beta-subunit association to factor binding. Reason: The literal PMID:31515488 record is a human EIF2B2βEIF2B4 two-hybrid interaction with a separately recorded variant that did not disrupt the tested association. The original Methods describe wild-type comparisons, autoactivation controls and repeated disruption scoring. Orthogonal PCA was performed on a selected subset, not independently established for this pair. The positive pair and verified factor class support GO:0031369. Proposed replacements: translation initiation factor binding Supporting Evidence: file:human/EIF2B4/EIF2B4-source-guide.md file:human/EIF2B4/EIF2B4-bioinformatics/RESULTS.md |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | MODIFY | Summary: Refine the HuRI beta-subunit association to factor binding. Reason: The HuRI records preserve human EIF2B2βEIF2B4 array, pooling and validated two-hybrid evidence. The original source describes pairwise quadruplicate retesting and sequence confirmation, with orthogonal assays used for selected network validation. A translation initiation factor partner supports GO:0031369 without requiring an additional purified-interface assay or claiming physiological regulation from the screen alone. Proposed replacements: translation initiation factor binding Supporting Evidence: file:human/EIF2B4/EIF2B4-source-guide.md file:human/EIF2B4/EIF2B4-bioinformatics/RESULTS.md |
| GO:0005515 protein binding | IPI PMID:32814053 Interactome Mapping Provides a Network of Neurodegenerative ... | KEEP AS NON CORE | Summary: Retain the positive angiotensinogen screen association. Reason: The literal PMID:32814053 records join EIF2B4 to human angiotensinogen P01019 in array, pooled and validated two-hybrid assays. The study retested candidate pairs, but its mammalian orthogonal assay covered a subset and has not been mapped to this pair. P01019 is the precursor reference protein; no processed angiotensin ligand identity is established for the tested insert. The positive association therefore remains generic and non-core under the ClinGen project protein-binding policy, without transferring hormone activity or inferring a native encounter. Supporting Evidence: file:human/EIF2B4/EIF2B4-source-guide.md file:human/EIF2B4/EIF2B4-bioinformatics/RESULTS.md |
| GO:0005515 protein binding | IPI PMID:33961781 Dual proteome-scale networks reveal cell-specific remodeling... | MODIFY | Summary: Refine the BioPlex beta-subunit association to factor binding. Reason: Source-specific anti-tag affinity-purification records join EIF2B4 and EIF2B2 in human HEK293T and HCT116 contexts. The original BioPlex Methods require reproducible peptide support and use abundance/frequency filters and CompPASS-Plus scoring, which reduce but do not eliminate background associations. These are complex-association data rather than proof of purified direct contact. The independently established beta factor class and the positive curated pair support GO:0031369; no unique-peptide sequences were independently re-audited. Proposed replacements: translation initiation factor binding Supporting Evidence: file:human/EIF2B4/EIF2B4-source-guide.md file:human/EIF2B4/EIF2B4-bioinformatics/RESULTS.md |
| GO:0005851 eukaryotic translation initiation factor 2B complex | IPI PMID:29599213 Structure of the nucleotide exchange factor eIF2B reveals me... | ACCEPT | Summary: Human delta is a structural constituent of eIF2B. Reason: The recovered PMID:29599213 original describes coexpression of human subunits, including the beta/delta construct, and structural and biochemical analysis of the assembled complex. Delta participates in the regulatory core and inter-tetramer interface. The evidence supports complex membership without assigning all complex catalysis to delta or extending the tested construct to every natural isoform. 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 file:human/EIF2B4/EIF2B4-source-guide.md |
| GO:0045948 positive regulation of translational initiation | IDA PMID:29599213 Structure of the nucleotide exchange factor eIF2B reveals me... | ACCEPT | Summary: Delta-dependent assembly positively regulates translation initiation. Reason: The human reconstitution study examines the delta L179V interface mutation, which stabilizes higher-order assembly and increases exchange activity without ISRIB, alongside the separate L179A pocket experiment. This is positive structural participation in regulation of the initiation machinery, not merely a downstream disease association. The effect belongs to the assembled complex; it is not evidence of isolated delta catalysis. 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 file:human/EIF2B4/EIF2B4-source-guide.md |
| GO:0002183 cytoplasmic translational initiation | IDA PMID:27023709 Expression, purification, and crystallization of Schizosacch... | ACCEPT | Summary: Retain the human-complex initiation evidence with its species limits. Reason: Although the principal recombinant construction and crystallization in PMID:27023709 use S. pombe eIF2B, the Methods and Results also report a human eIF2/human eIF2B comparator in a reconstituted translation system. That positive human whole-complex experiment supports the delta subunitβs participation in cytoplasmic initiation. It does not establish a human delta-only catalytic assay. |
| GO:0005085 guanyl-nucleotide exchange factor activity | IDA PMID:25858979 Stress responses. Mutations in a translation initiation fact... | ACCEPT | Summary: Retain delta GEF participation and query the source relation. Reason: The inspected original main text and captions report hamster CHO Eif2b4 mutations that alter ISRIB responses and whole-eIF2B GDP exchange. These are genuine delta-specific perturbations and positive regulatory evidence. Independent human structure and reconstitution place delta at the regulatory assembly and ISRIB pocket. They support contribution to complex exchange rather than attributing the complete exchange reaction to delta; the imported enables relation is retained pending a conditional curator check. Supplementary Methods were unavailable. 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 file:human/EIF2B4/EIF2B4-source-guide.md |
| GO:0005085 guanyl-nucleotide exchange factor activity | IDA PMID:27023709 Expression, purification, and crystallization of Schizosacch... | ACCEPT | Summary: Retain the complex exchange contribution with a source-specific relation query. Reason: The original PMID:27023709 chiefly characterizes S. pombe complexes and includes a human whole-complex translation comparator. Together with independent human reconstitution it supports delta as a structural/regulatory participant in eIF2B exchange. The specific human comparator is not a delta-resolved nucleotide-exchange assay, so the enables versus contributes_to relation merits a conditional curator query while the positive annotation and imported relation are preserved. |
| GO:0005851 eukaryotic translation initiation factor 2B complex | IDA PMID:27023709 Expression, purification, and crystallization of Schizosacch... | ACCEPT | Summary: The human comparator supports eIF2B complex membership. Reason: The source is not restricted to the S. pombe preparation named in its title: it also reports a human eIF2B comparator. Membership of human delta in eIF2B is independently demonstrated by human reconstitution and structures. Retain the curatorβs complex assertion while keeping the principal sourceβs structural organism and whole-complex assay scope explicit. |
| GO:0050852 T cell receptor signaling pathway | IDA PMID:8626696 T-cell activation leads to rapid stimulation of translation ... | UNDECIDED | Summary: The source-specific T-cell receptor signaling role remains unresolved. Reason: Selected original Results establish activation of whole eIF2B exchange downstream of stimulation in primary human T cells, using ionomycin/PMA and a similar PHA response. Those measurements do not resolve which work EIF2B4 performs in the T-cell receptor signaling process itself. Complete Experimental Procedures were not recovered. Preserve the curatorβs source assertion as UNDECIDED rather than treating downstream translation activation as sufficient participation, or requiring an isolated delta assay. This does not reject the positive whole-complex response or the established translation role. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-72670 | ACCEPT | Summary: The modeled human delta entity is explicitly cytosolic. Reason: The literal Reactome chain is R-HSA-72670 input eIF2B 72526 to component 72521, whose reference entity is human UniProt Q9UI10 residues 1β523 and whose own compartment is cytosol. This is target-resolved localization, not inference from the compartment of an unrelated reaction. The same complex participates in the eIF2:GDP intermediate. Supporting Evidence: Reactome:R-HSA-72670 Formation of eIF2:GDP:eIF2B intermediate file:human/EIF2B4/EIF2B4-source-guide.md file:human/EIF2B4/EIF2B4-bioinformatics/RESULTS.md |
| GO:0005829 cytosol | TAS Reactome:R-HSA-72722 | ACCEPT | Summary: The activation model retains cytosolic human delta. Reason: R-HSA-72722 links the eIF2:GDP:eIF2B input and eIF2B output to complex 72526 and human Q9UI10 component 72521. Both the target component and complex are cytosolic. Catalyst 72528 represents the eIF2B complex, so this localization evidence does not assign autonomous exchange chemistry to delta. 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. file:human/EIF2B4/EIF2B4-source-guide.md file:human/EIF2B4/EIF2B4-bioinformatics/RESULTS.md |
| GO:0031369 translation initiation factor binding | ISS GO_REF:0000024 | ACCEPT | Summary: The rat donor supports conserved initiation-factor binding. Reason: The complete rat Q63186 record maps this term to direct IDA evidence PMID:9446619. Selected original Methods, Results and figure captions show rat-liver eIF2/eIF2B preparations and far-Western binding of eIF2 to delta and epsilon; recombinant rat eIF2 subunits were expressed in Sf9 cells. This provides actual donor grounding for the curated human ISS transfer, corroborated by human factor assembly. The membrane-overlay assay is not a demonstration of a native isolated human binary complex. Supporting Evidence: file:human/EIF2B4/EIF2B4-source-guide.md file:human/EIF2B4/EIF2B4-bioinformatics/RESULTS.md |
| GO:0006413 translational initiation | IDA PMID:16289705 An efficient mammalian cell-free translation system suppleme... | MODIFY | Summary: Specify the cytoplasmic initiation process. Reason: The authentic PMID:16289705 abstract describes a mammalian cell-free translation system in which added initiation factors, including eIF2B, enhance translation. Its complete operative body was not recovered, but the factorβs role is independently established by human reconstitution, so the experimental claim is not rejected. Cytoplasmic translational initiation is the supported specific process; no delta-only enhancement assay is asserted. Proposed replacements: cytoplasmic translational initiation 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. file:human/EIF2B4/EIF2B4-source-guide.md |
| GO:0009408 response to heat | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Retain the conserved heat-response context with donor limits. Reason: The complete Q63186 donor query maps this ISS assertion to PMID:9341116 IDA. Its authentic abstract reports heat-dependent changes in whole-eIF2B activity in rat H35 hepatoma cells that track translation inhibition and recovery. The evidence supports regulation of the delta-containing factor in a heat response, without identifying delta as a temperature sensor. The curator-supported transfer is retained as non-core; the donorβs full operative body remains unavailable. Supporting Evidence: file:human/EIF2B4/EIF2B4-source-guide.md file:human/EIF2B4/EIF2B4-bioinformatics/RESULTS.md |
| GO:0009408 response to heat | TAS PMID:12499492 A severe variant of childhood ataxia with central hypomyelin... | KEEP AS NON CORE | Summary: Retain the conserved heat-response context with explicit source limits. Reason: The response-to-heat annotation is retained as a non-core, stress-dependent context for delta-containing eIF2B. Independent experimental grounding comes from the rat Q63186 IDA record linked to PMID:9341116, whose authentic abstract reports heat-dependent changes in whole-eIF2B activity during heat shock and recovery. This supports the conserved factor's participation without establishing delta as a temperature sensor or a direct human delta perturbation. The exact delta-specific evidence behind clinical PMID:12499492 remains unverified because only its authentic abstract was accessible. The original TAS citation is retained; the corroboration does not authenticate that paper's complete experiments. |
| GO:0014003 oligodendrocyte development | IMP PMID:15217090 The life and death of oligodendrocytes in vanishing white ma... | UNDECIDED | Summary: The delta-specific oligodendrocyte claim is not resolved by the inspected cohort. Reason: The recovered Methods, clinical table and selected Results of PMID:15217090 describe oligodendrocyte density and apoptosis in VWM autopsy tissue. The reported patients 1β4 have EIF2B5 genotypes and patient 5 has EIF2B2, and the discussion does not establish a delta-specific developmental perturbation. The observations support eIF2B-associated pathology but leave this particular EIF2B4 IMP assertion unresolved. Retain the source as UNDECIDED rather than declaring a misattribution from title or incomplete access. 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. file:human/EIF2B4/EIF2B4-source-guide.md |
| GO:0003743 translation initiation factor activity | IDA PMID:16289705 An efficient mammalian cell-free translation system suppleme... | ACCEPT | Summary: Retain the explicit contribution to initiation factor activity. Reason: The imported contributes_to qualifier already expresses a subunit contribution to the factorβs activity. The mammalian cell-free studyβs abstract and independent human-complex reconstitution support that scope. Complete source Methods were unavailable, but the assertion is clearly compatible with established delta function; there is no basis to reject the curator-supported contribution. 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. file:human/EIF2B4/EIF2B4-source-guide.md |
| GO:0009749 response to glucose | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Retain the glucose-responsive translation context. Reason: The rat Q63186 IDA donor maps to PMID:8567668. Its authentic abstract measures rapid glucose stimulation of whole-eIF2B activity in isolated rat islets, with a nonmetabolizable glucose analogue as a negative comparator and no change in eIF2alpha phosphorylation. This grounds a conserved response context for the complex, not a demonstrated delta glucose-binding or sensing activity. Retain the curated ISS assertion as non-core with full donor-body access unresolved. Supporting Evidence: file:human/EIF2B4/EIF2B4-source-guide.md file:human/EIF2B4/EIF2B4-bioinformatics/RESULTS.md |
| GO:0043434 response to peptide hormone | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Retain the peptide-hormone response context with its actual donor scope. Reason: The rat Q63186 record maps to PMID:8430778 IDA. The authentic abstract examines diabetic rat muscle, altered whole-eIF2B activity and candidate CKII/redox regulation; it does not independently establish a delta-specific insulin receptor mechanism. The original curatorβs hormone-response transfer remains plausible in this complex context and is retained as non-core. Complete Methods and the precise hormone-treatment experiment were not recovered, so no stronger mechanistic claim is made. Supporting Evidence: file:human/EIF2B4/EIF2B4-source-guide.md file:human/EIF2B4/EIF2B4-bioinformatics/RESULTS.md |
| GO:0005515 protein binding | IPI PMID:15060152 Mutations linked to leukoencephalopathy with vanishing white... | MODIFY | Summary: Refine beta-containing complex association to factor binding. Reason: The recovered PMID:15060152 original uses sequenced human subunit cDNAs in HEK293 cells and tagged-subunit copurification. In the isolated combinations, beta did not show association with the individual other subunits; that negative result is not presented as a positive binary betaβdelta assay. The same study positively recovers stable beta/gamma/delta/epsilon and five-subunit assemblies. Together with the independent human beta/delta interface in PMID:29599213, those positive associations support GO:0031369 without requiring or claiming a purified binary interface in PMID:15060152. Proposed replacements: translation initiation factor binding Supporting Evidence: file:human/EIF2B4/EIF2B4-source-guide.md file:human/EIF2B4/EIF2B4-bioinformatics/RESULTS.md |
| GO:0001541 ovarian follicle development | IMP PMID:15507143 Screening for known mutations in EIF2B genes in a large pane... | MARK AS OVER ANNOTATED | Summary: Ovarian dysgenesis is supported; a follicle-development role is over-specific. Reason: The complete operative PMID:15507143 Methods and Results report no screened known EIF2B mutation among 93 women with isolated premature ovarian failure. Its Discussion refers to earlier ovarioleukodystrophy and proposes follicle apoptosis as a possible explanation; neither is a positive follicle-development experiment in this cohort. Independently inspected PMID:14566705 patient 6 and Table 1 document homozygous EIF2B4 A391D and ovarian dysgenesis at autopsy. That is positive human ovarian disease evidence, but it does not resolve follicle formation or maturation, the process specified by GO:0001541, or a particular step contributed by EIF2B4. Mark the narrower process claim as over-annotated while retaining the clinical findings. This is not a wrong-gene conclusion, a demonstrated absence of ovarian function, or a confirmed wrong-reference defect; the original citation is preserved. Supporting Evidence: 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%) file:human/EIF2B4/EIF2B4-source-guide.md |
| GO:0005085 guanyl-nucleotide exchange factor activity | IDA PMID:11323413 Characterization of the mammalian initiation factor eIF2B co... | ACCEPT | Summary: Retain the explicit contribution to exchange activity. Reason: The original Methods purify native eIF2B from human HeLa cytoplasm and assay GDP release by the assembled factor. Delta is one of the subunits in the active preparation. The imported contributes_to relation accurately expresses that positive complex-level participation. Separate recombinant alpha/beta experiments in the paper are not attributed to delta. 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 file:human/EIF2B4/EIF2B4-source-guide.md |
| GO:0005737 cytoplasm | IDA PMID:11323413 Characterization of the mammalian initiation factor eIF2B co... | MODIFY | Summary: Refine the supported cytoplasmic location to cytosol. Reason: The original PMID:11323413 Methods purify active native eIF2B, including delta, from HeLa cytoplasm. That preparation supports the broad imported location but does not by itself resolve a finer compartment. Independent target-resolved Reactome chains identify human Q9UI10 component 72521 as cytosolic, corroborating the UniProt cytosol mapping. GO:0005829 is therefore a supported refinement; the source is not characterized as incorrect. Proposed replacements: cytosol Supporting Evidence: file:human/EIF2B4/EIF2B4-source-guide.md file:human/EIF2B4/EIF2B4-bioinformatics/RESULTS.md |
| GO:0005851 eukaryotic translation initiation factor 2B complex | IDA PMID:11323413 Characterization of the mammalian initiation factor eIF2B co... | ACCEPT | Summary: Native human eIF2B contains delta. Reason: The Methods and Results identify the five-subunit native human factor purified from HeLa cytoplasm and recovered as an exchange-active preparation. Delta complex membership is directly compatible with this experiment and corroborated by later human reconstitution; no autonomous delta catalytic claim is needed. 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 file:human/EIF2B4/EIF2B4-source-guide.md |
| GO:0042552 myelination | IMP PMID:14566705 eIF2B-related disorders: antenatal onset and involvement of ... | KEEP AS NON CORE | Summary: Retain the delta-associated myelination phenotype as non-core. Reason: The selected original PMID:14566705 clinical and genotype table contains biallelic EIF2B4 cases with severe cerebral white-matter abnormalities and multisystem involvement. Those human delta-specific cases support the disease-associated myelination context. The paperβs displayed MRI examples include other subunits and are not relabeled as delta data. The phenotype is retained outside the core exchange mechanism, without claiming a distinct delta myelin-synthesis enzyme. |
| GO:0005085 guanyl-nucleotide exchange factor activity | IMP PMID:15054402 Decreased guanine nucleotide exchange factor activity in eIF... | ACCEPT | Summary: Human delta variants impair whole-complex exchange. Reason: PMID:15054402 measures GDP dissociation from rat-liver eIF2 using human patient lymphoblast extracts. Table 1 includes EIF2B4 R209Q, P243L and R374C cases with reduced exchange compared with controls, with substantial variant-dependent residual activity. These are direct human delta-genotype effects on complex function. The imported contributes_to qualifier is appropriate and is preserved; the assay is not delta-only catalysis. 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. file:human/EIF2B4/EIF2B4-source-guide.md |
| GO:0005851 eukaryotic translation initiation factor 2B complex | IDA PMID:15060152 Mutations linked to leukoencephalopathy with vanishing white... | ACCEPT | Summary: Human subunit copurification supports complex membership. Reason: Sequenced human subunit constructs coexpressed in HEK293 cells form stable beta/gamma/delta/epsilon and five-subunit assemblies in the recovered PMID:15060152 experiments. Deltaβs membership is supported even though incomplete combinations and endogenous subunit bridging limit interpretation of some pairwise tests. No fixed natural-isoform equivalence is assumed. |
| GO:0006417 regulation of translation | NAS PMID:12556349 Reduced amino acid availability inhibits muscle protein synt... | ACCEPT | Summary: Translation regulation is integral to the delta-containing factor. Reason: The authentic PMID:12556349 abstract concerns amino-acid depletion and replacement in swine skeletal muscle and measures whole-eIF2B exchange alongside protein synthesis. It does not demonstrate a human delta-only nutrient sensor. The NAS assertion is nevertheless biologically supported by deltaβs established structural/regulatory contribution and human interface-mutant effects on factor activity, so regulation of translation is retained. This broader source assertion and the separately supported positive-initiation assertion describe the same integrated translation mechanism at different resolutions; they do not create two independent core functions. Supporting Evidence: 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 file:human/EIF2B4/EIF2B4-source-guide.md |
| GO:0005515 protein binding | IPI PMID:15060152 Mutations linked to leukoencephalopathy with vanishing white... | MODIFY | Summary: Refine the epsilon-containing association to factor binding. Reason: The recovered human coexpression study shows delta and epsilon within stable eIF2B assemblies. It also reports that epsilon alone did not strongly pull down isolated delta in the tested two-subunit combination, so a purified binary interaction is not inferred. The positive complex association, later human structures and epsilonβs established initiation-factor class support GO:0031369 without transferring epsilon catalytic activity to delta. Proposed replacements: translation initiation factor binding Supporting Evidence: file:human/EIF2B4/EIF2B4-source-guide.md file:human/EIF2B4/EIF2B4-bioinformatics/RESULTS.md |
| GO:0005515 protein binding | IPI PMID:29599213 Structure of the nucleotide exchange factor eIF2B reveals me... | MODIFY | Summary: Refine the human beta/delta structural association. Reason: The PMID:29599213 original describes a human beta/delta expression construct and resolved regulatory-core assembly, with delta L179 substitutions affecting the interface and higher-order assembly. This is positive association with EIF2B2, an independently established initiation-factor subunit. GO:0031369 captures the partner class, without claiming that every natural delta isoform was tested. Proposed replacements: translation initiation factor binding Supporting Evidence: file:human/EIF2B4/EIF2B4-source-guide.md file:human/EIF2B4/EIF2B4-bioinformatics/RESULTS.md |
| GO:0005515 protein binding | IPI PMID:32814053 Interactome Mapping Provides a Network of Neurodegenerative ... | KEEP AS NON CORE | Summary: Retain the positive FOS binary interaction as non-core generic binding. Reason: The literal human FOS P01100βEIF2B4 records include array, pooled and validated two-hybrid assays. The binary reporter evidence and source-described pairwise retesting support the assay-context interaction. Independently reviewed FOS function identifies DNA binding in the AP-1 complex, but the publication used ORFs or fragments and neither reference checksums nor blank feature fields verify the actual insert or natural isoform. No target-pair orthogonal result or independently established EIF2B4 transcriptional role was recovered. Retain the positive generic binding as non-core; partner class alone is not taken as sufficient functional specificity for GO:0140297 in this unresolved construct context. This is not an artefact or compartment-based rejection. Supporting Evidence: file:human/EIF2B4/EIF2B4-source-guide.md file:human/EIF2B4/EIF2B4-bioinformatics/RESULTS.md |
| GO:0005515 protein binding | IPI PMID:32814053 Interactome Mapping Provides a Network of Neurodegenerative ... | KEEP AS NON CORE | Summary: Retain the positive KLKB1 binary interaction as non-core generic binding. Reason: The literal human KLKB1 P03952βEIF2B4 pair is positive in array, pooled and validated two-hybrid records. These binary assays support interaction with the identified partner. The official reference is a protease precursor with separate heavy and light chains, with the S1 protease domain in the light chain. The exact screened insert, maturation state and presence of the catalytic-domain-containing portion were not established from the source ORF/fragment collection. No independently established EIF2B4 role with kallikrein was recovered. Retain the supported generic interaction as non-core, rather than assigning GO:0002020 from the mature reference-protein class. This does not declare the hit false, require catalytic-site binding or infer incompatibility from plasma localization. Supporting Evidence: file:human/EIF2B4/EIF2B4-source-guide.md file:human/EIF2B4/EIF2B4-bioinformatics/RESULTS.md |
| GO:0005515 protein binding | IPI PMID:32814053 Interactome Mapping Provides a Network of Neurodegenerative ... | KEEP AS NON CORE | Summary: Retain the positive LPL binary interaction as non-core generic binding. Reason: The literal human LPL P06858βEIF2B4 records include array, pooled and validated two-hybrid assays. These binary assays support the interaction, and the independently reviewed reference protein is a lipase with a signal peptide and mature chain. The exact tested insert, processing state and natural isoform were not verified from the ORF/fragment collection; no target-pair orthogonal result or independently established EIF2B4 role with LPL was recovered. Retain generic binding as non-core because this evidence does not settle the proposed lipase-binding functional specificity. No false-hit conclusion or native-compartment disproof is made, and lipid hydrolysis or lipase regulation is not assigned to EIF2B4. Supporting Evidence: file:human/EIF2B4/EIF2B4-source-guide.md file:human/EIF2B4/EIF2B4-bioinformatics/RESULTS.md |
| GO:0005515 protein binding | IPI PMID:32814053 Interactome Mapping Provides a Network of Neurodegenerative ... | KEEP AS NON CORE | Summary: Retain the positive complex III core-protein association. Reason: The literal PMID:32814053 records support a human UQCRC1 P31930βEIF2B4 two-hybrid association. The reviewed partner record establishes respiratory complex III membership, whereas its processing-protease description is qualified by similarity or probability. That is insufficient here for a confident protease-binding refinement. The positive interaction is retained as generic non-core binding under project policy, not removed because a native mitochondrial/cytosolic encounter was not measured. Supporting Evidence: file:human/EIF2B4/EIF2B4-source-guide.md file:human/EIF2B4/EIF2B4-bioinformatics/RESULTS.md |
| GO:0005515 protein binding | IPI PMID:32814053 Interactome Mapping Provides a Network of Neurodegenerative ... | KEEP AS NON CORE | Summary: Retain the isoform-specific VHL screen association. Reason: The literal partner is P40337-2, whose authentic 172-residue sequence deletes canonical residues 114β154; it is not the short N-terminally truncated VHL isoform 3. Its curated reference checksum matches that exact isoform. The positive two-hybrid association is retained. General descriptions of VHL as a substrate-recruiting E3-complex component do not establish catalytic enzyme activity of this specific product, so no ligase-binding or transferred adaptor-function claim is added. Supporting Evidence: file:human/EIF2B4/EIF2B4-source-guide.md file:human/EIF2B4/EIF2B4-bioinformatics/RESULTS.md |
| GO:0005515 protein binding | IPI PMID:32814053 Interactome Mapping Provides a Network of Neurodegenerative ... | KEEP AS NON CORE | Summary: Retain the positive GATM binary interaction as non-core generic binding. Reason: The literal human GATM P50440βEIF2B4 pair occurs in array, pooled and validated two-hybrid records. These binary assays support the pair. Independently reviewed GATM is a transamidinase, with an N-terminal mitochondrial targeting sequence in the reference protein; the exact screened insert, processing state and natural isoform remain unverified. Without an independently established EIF2B4 role with GATM, retain the supported assay-context association as generic non-core binding rather than deriving GO:0019899 solely from the reference partner class. This neither rejects the positive screen nor transfers catalysis, creatine biosynthesis or a native mitochondrial role to EIF2B4. Supporting Evidence: file:human/EIF2B4/EIF2B4-source-guide.md file:human/EIF2B4/EIF2B4-bioinformatics/RESULTS.md |
| GO:0005515 protein binding | IPI PMID:32814053 Interactome Mapping Provides a Network of Neurodegenerative ... | KEEP AS NON CORE | Summary: Retain the positive GRB2 association without an invented function. Reason: The literal PMID:32814053 records join human GRB2 P62993 to EIF2B4 in screened and validated two-hybrid assays. GRB2 is a nonenzymatic signaling adaptor; that fact alone does not supply a supported narrower binding subclass or establish adaptor activity of EIF2B4. The association remains generic non-core binding under the explicit ClinGen project policy, with the same positive-screen standard used for the class-refined partners. Supporting Evidence: file:human/EIF2B4/EIF2B4-source-guide.md file:human/EIF2B4/EIF2B4-bioinformatics/RESULTS.md |
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Download this section (compressed HTML)Q: Do the sequence-verified 523-, 543- and 522-residue human EIF2B4 products differ in eIF2B assembly, nucleotide exchange or responsiveness to phosphorylated eIF2 at matched near-endogenous expression? The 543-residue construct called V1 in PMID:37014850 is not assigned to a natural UniProt product by length alone.
Q: In the human cell contexts studied in PMID:37014850, does elevated delta alter phosphorylated-eIF2 sequestration by a free delta pool, the abundance of gamma/epsilon subcomplexes, or another assembly state? The reported gradient, co-immunoprecipitation and extract exchange measurements do not distinguish these mechanisms.
Experiment: Compare sequence-verified 523-, 543- and 522-residue products in matched-expression rescue and reconstituted human eIF2B. Quantify free subunits and assembled-complex stoichiometry together with eIF2 binding, GDP release and responses to phosphorylated eIF2. Include canonical-product rescue, delta omission and matched assembled-complex concentrations to distinguish altered assembly from changes in regulation.
Hypothesis: Natural EIF2B4 products may differ in complex assembly or phosphorylation-sensitive regulation; sequence differences alone do not establish an effect or its direction.
Type: Matched-product rescue and biochemical reconstitution
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