EIF2B3

Summary: EIF2B3 contributes to cytoplasmic translation initiation as an inherited eIF2B gamma-subunit function.

Reason: The current PTHR45989 tree places the exact 452-residue human sequence below PTN000501033. The literal IBD for cytoplasmic translational initiation is at that ancestor, with human Q9NR50 and PomBase SPAC4D7.09 evidence. No same-term loss record occurs along the target path. The human target is legitimate descendant evidence, not circular support. Human eIF2B stimulates HCV-IRES-directed translation in the reconstituted system of PMID:27023709, consistent with this conserved placement.

Summary: Human eIF2B supports cytoplasmic initiation in a reconstituted translation assay.

Reason: PMID:27023709 Methods and Figure 2h explicitly compare human eIF2B with recombinant Schizosaccharomyces pombe eIF2B in a human HCV-IRES luciferase translation system. Both enhance translation. The human comparator supports EIF2B3 as a component of the initiation factor; the extensive expression, crystallization and mutant-complex work in this paper concerns S. pombe and is not relabeled as an isolated human gamma assay.

Summary: EIF2B3 contributes to translation initiation in human HCV-IRES reporter assays.

Reason: PMID:10900014 independently targets human EIF2B gamma transcripts in HeLa cells with multiple active and inactive ribozymes. Reduced HCV-IRES-dependent expression despite maintained or increased reporter RNA supports a translation-factor contribution. The paper separately targets EIF2 gamma, a different protein. Its cloned human EIF2B gamma is reported as 452 residues, but length alone does not authenticate equivalence to every current natural product. The preserved contributes_to claim does not assert autonomous gamma activity.

Summary: EIF2B3 contributes to the initiation-factor activity of eIF2B.

Reason: The verified abstract of PMID:16289705 reports that supplementation of HeLa extracts with eIF2B enhances capped, uncapped and EMCV-IRES-promoted translation. This positive whole-factor result and independent human gamma-containing reconstitution support the curated contributes_to annotation. The operative full Methods were not recovered, so the eIF2B preparation species, tags and exact gamma insert are not inferred from the human extract alone.

Summary: The conserved gamma subunit contributes to eIF2B guanyl-nucleotide exchange activity.

Reason: The exact human sequence descends from PTN000501033 in the current PTHR45989 tree and alignment. The literal GO:0005085 IBD at that node cites PomBase SPAC4D7.09; current P56288 records include experimentally curated exchange-factor evidence from PMID:26901872. A single donor does not weaken this phylogenetic judgment. Human gamma-containing complexes and an EIF2B3 patient genotype independently support participation in exchange; this does not identify gamma as the isolated catalytic epsilon subunit.

Summary: EIF2B3 contributes to the exchange activity of native human eIF2B.

Reason: PMID:11323413 Methods purify eIF2B from HeLa cytoplasm. The Results describe a five-polypeptide preparation depleted of substrate eIF2 that releases labeled GDP from eIF2 and supports exchange in the presence of free nucleotide. This supports the preserved contributes_to claim for gamma in the complex. The separate nucleotide cross-linking and recombinant-subunit experiments concern beta and do not establish gamma nucleotide binding or isolated gamma catalysis.

Summary: EIF2B3 is a functional component of the eIF2B exchange factor.

Reason: The independently assessed PMID:25858979 experiments measure fluorescent GDP exchange by whole eIF2B and its response to ISRIB. They support gamma as a component of the active complex, not an isolated gamma exchange assay or a gamma-specific ISRIB-binding site. The exact gamma insert and the exception to the reported coding-sequence description in unread Table S1 remain unresolved; no claim of universal wild-type or natural-isoform equivalence is made.

Summary: EIF2B3 participates in the exchange-factor complex that supports initiation.

Reason: PMID:27023709 directly demonstrates human eIF2B enhancement of HCV-IRES translation and constructs the homologous S. pombe gamma-epsilon subcomplex and holocomplex. Its human comparator is a translation assay, not a purified human gamma GDP-release assay. Together with native human and recombinant human eIF2B exchange measurements, this supports the curated exchange-factor function at the subunit-contribution level.

Summary: The gamma-family rule correctly assigns participation in eIF2B exchange activity.

Reason: Current ARBA00028188 condition set 33 is satisfied by both literal EIF2B3 FunFam matches, 2.160.10.10:FF:000031 and 3.90.550.10:FF:000105, together with Eutheria lineage membership. This is a gamma-family assignment consistent with human biochemical and clinical evidence. It does not establish isolated gamma catalysis.

Summary: An EIF2B3 disease variant reduces cellular eIF2B exchange activity.

Reason: PMID:15054402 Table 1 identifies patient 823 with homozygous EIF2B3 H341Q and whole-cell exchange activity of 61 ± 6 percent of control. Methods use EBV-transformed human lymphocytes and GDP-loaded rat-liver eIF2 as substrate. The measured loss supports gamma contribution to eIF2B function, as the preserved contributes_to qualifier asserts; it is not a purified gamma reaction or a direct assay of all three natural products.

Summary: Human EIF2B gamma associates with the epsilon translation-initiation-factor subunit.

Reason: PMID:15060152 expresses tagged human subunits in HEK293 cells and recovers gamma with His-myc-tagged epsilon by affinity purification. Gamma and epsilon form a binary subcomplex, and gamma is required for epsilon association with the other subunits in the tested combinations. EIF2B5/Q13144 is independently established as a translation initiation factor, so GO:0031369 captures the supported partner class. This is a cell-lysate subcomplex assay, not a claim of purified binary affinity, a mapped interface, or equivalence of all natural gamma products.

Proposed replacements: translation initiation factor binding

Summary: A human cytosolic EIF2B3 pool supports refinement of the broad cytoplasmic localization.

Reason: PMID:11323413 purifies native gamma-containing eIF2B from HeLa cytoplasm, establishing the broad cytoplasmic pool but not resolving cytosol by that fractionation alone. Independently, the human EIF2B3 HPA subcellular record assigns the cytosol location itself supported reliability, and Reactome traces canonical Q9NR50 within cytosolic eIF2B. Refine the correct but broad term to GO:0005829, already independently supported in this review. This does not imply exclusive localization or equal localization of the three natural products.

Proposed replacements: cytosol

Summary: Human EIF2B3 has a supported cytosolic pool.

Reason: The current Human Protein Atlas EIF2B3 subcellular page assigns the human cytosol location itself a supported reliability level. HPA024219 reports cytosolic staining in A-431, U-251MG and U2OS cells; this is not an inference from the overall gene reliability score. The assay does not resolve the three natural products, and image pixels were not independently assessed.

Summary: The UniProt cytosol mapping agrees with direct localization and biochemical evidence.

Reason: The SL-0091 location mapping assigns a cytosolic pool to EIF2B3. Native eIF2B purification from HeLa cytoplasm and the location-specific supported HPA cytosol annotation agree with that mapping. Cytosol is a normal site of the exchange-factor mechanism, without implying localization is exclusive or identical for every product.

Summary: EIF2B3 is a cytosolic component in the eIF2-GDP-eIF2B intermediate.

Reason: The official Reactome source traces event 72670 input 72526 (eIF2B complex) through hasComponent to entity 72525, human Q9NR50 residues 1–452, explicitly in GO:0005829. This literal target chain supports the cytosol location; it is a curated reaction-model assertion, not an independently read primary experiment or a claim about the shorter natural products.

Summary: EIF2B3 is retained in the cytosolic eIF2 activation cycle.

Reason: Reactome event 72722 releases the eIF2B complex as output 72526; that complex contains human Q9NR50 entity 72525 at GO:0005829. The target-specific chain supports cytosol location in nucleotide exchange. It does not transfer substrate eIF2 gamma identity or GTP hydrolysis to EIF2B gamma.

Summary: EIF2B complex membership is a conserved gamma-subunit property.

Reason: The human target sequence is exactly represented in the current PTHR45989 alignment and descends from the literal PTN000501033 GO:0005851 IBD. That IBD includes PomBase, rat, yeast and human descendant evidence; no same-term loss record occurs on the target path. Human self-evidence is expected and is corroborated by gamma-containing native and recombinant complexes.

Summary: EIF2B3 is a subunit of native human eIF2B.

Reason: PMID:11323413 purifies a five-polypeptide, exchange-active eIF2B preparation from HeLa cytoplasm and distinguishes it from substrate eIF2. This supports complex membership; the beta-specific cross-linking experiments are not required to assign gamma membership and are not transferred to gamma.

Summary: Human gamma participates in assembly of the eIF2B complex.

Reason: PMID:15060152 uses human EIF2B3 cDNA from HEK293 RNA and tagged-subunit affinity purifications in HEK293 cells. Gamma associates with epsilon and is present in the beta-gamma-delta-epsilon and five-subunit complexes. The Results explicitly distinguish these combinations from unstable or absent subcomplexes, providing source-specific gamma membership evidence.

Summary: EIF2B3 is retained as a component of the active human eIF2B comparator.

Reason: The human eIF2B preparation used in PMID:27023709 stimulates the reconstituted human translation system. The extensive recombinant purification and structural work in the same paper is S. pombe, including its gamma-epsilon subcomplex. The human membership claim is consistent with independent tagged-human assembly and human structural reconstitution; no fungal structure is presented as a direct human gamma structure.

Summary: The current gamma-family rule supports eIF2B complex membership.

Reason: ARBA00088579 condition set 2 is literally satisfied by the two current gamma FunFam matches and Metazoa lineage membership. The assigned complex is independently supported by human tagged-subunit assembly and recombinant human eIF2B. The sequence match is used as a rule premise, not as evidence that all alternative products have identical activity.

Summary: Recombinant human eIF2B contains the gamma subunit.

Reason: PMID:29599213 coexpresses all five human subunits in E. coli, purifies a decameric complex and characterizes its assembly and GDP-exchange activity. Methods explicitly identify EIF2B3 as the gamma gene in the expression plasmid. This supports complex membership; the synthesized insert sequences in supplementary material were not independently read, and the gamma chain is not equated with all natural products.

Summary: EIF2B3 acts specifically at cytoplasmic translation initiation.

Reason: ARBA00027100 condition set 68 matches both gamma FunFams and provides a sound broad translation assignment. Human initiation assays and the conserved eIF2B exchange mechanism identify the more specific initiation step. GO:0002183 is under both translational initiation and translation in the captured current typed ancestry.

Proposed replacements: cytoplasmic translational initiation

Summary: Human EIF2B3 supports cytoplasmic HCV-IRES-dependent initiation.

Reason: PMID:10900014 tests HCV-IRES reporters and independent ribozyme-mediated depletion of EIF2B gamma in human HeLa cells. Reporter RNA and bulk cap-dependent translation controls distinguish the measured IRES translation phenotype. Cytoplasmic translational initiation is the supported specific process; the paper does not establish a separate ribosomal RNA-binding activity of gamma.

Proposed replacements: cytoplasmic translational initiation

Summary: The supported initiation activity occurs in a mammalian cytoplasmic translation system.

Reason: The verified PMID:16289705 abstract reports enhanced capped, uncapped and EMCV-IRES-promoted translation after eIF2B supplementation of HeLa extracts. Cytoplasmic translational initiation is more specific than generic initiation and agrees with independent reconstitution. The unrecovered Methods limit the preparation and gamma-insert claims, not the positively reported compartment and initiation endpoint.

Proposed replacements: cytoplasmic translational initiation

Summary: The electronic CNS-development assignment exceeds the demonstrated disease-associated translation defect.

Reason: ARBA00026561 condition set 51 matches the two EIF2B3 gamma FunFams, establishing why the electronic rule fires but not independently demonstrating a developmental activity. GO:0007417 concerns progression of the central nervous system from formation to its mature structure. PMID:15054402 provides positive human disease and biochemical evidence: patient 823 carries EIF2B3 H341Q, and the experiment measures reduced whole-eIF2B nucleotide exchange in EBV-transformed lymphocytes using rat-liver eIF2 substrate. Those observations establish disease relevance and impaired translation-factor function, rather than a gamma contribution to an identified CNS developmental step. Mark this electronic developmental inference as over-annotated; do not infer that EIF2B3 is irrelevant to nervous-system health or exclude an eventual demonstrated developmental role.

Summary: Human EIF2B gamma supports HCV-IRES translation, but its contribution to the RNA-binding function of the eIF2B complex remains unresolved.

Reason: The imported contributes_to relation permits participation in a molecular function executed by the eIF2B complex; it does not require an isolated gamma subunit to bind RNA. PMID:10900014 establishes human EIF2B gamma-dependent HCV-IRES translation and cites PMID:1647211 for earlier EMCV-IRES binding. The authenticated abstract of that earlier paper reports positive RNA competition in rabbit reticulocyte lysates and binding capacity attributed to the combined designation eIF-2/2B. Its full Methods and Results remain unavailable, so the factor preparation, direct RNA-contacting entity and gamma contribution are unresolved; the designation alone does not establish a mixed preparation. The current human knockdown experiments do not distinguish a gamma contribution required for RNA binding from its exchange-factor or assembly role. Retain the positive complex-level possibility as UNDECIDED rather than declaring RNA binding absent or replacing the molecular function. The separate EIF2 gamma experiments and ribozyme-mediated RNA cleavage do not measure EIF2B gamma RNA contact. The current GO hierarchy does not entail this RNA-binding activity from GO:0003743. QuickGO records deletion of the GO:0003743 is_a GO:0008135 relation on 2025-02-12; both now have GO:0180051 as an ancestor. Their current is_a ancestor sets and the dated relation history are preserved in EIF2B3-evidence/ontology-review.json. Thus accepting contributes_to translation initiation factor activity does not settle the distinct RNA-binding claim. The source-specific access limitation remains.

Summary: The rat ortholog provides a contextual heat-response annotation.

Reason: The current P70541 donor record for GO:0009408 is IDA PMID:9341116. Its verified abstract reports whole eIF2B activity changes correlated with translation inhibition during and after heat shock in rat hepatoma cells. This supports the curated ortholog transfer as a contextual translation response, without a human gamma-specific heat-sensing or isolated gamma thermosensitivity claim. The full operative donor paper was not recovered.

Summary: Heat-responsive eIF2B activity supports the non-core gene-level claim, while this clinical citation remains incompletely resolved.

Reason: The same EIF2B3 heat-response claim is supported independently by the curated rat P70541 transfer and its PMID:9341116 whole-eIF2B activity observations during and after heat shock. Retain the broad response as non-core, consistent with the ISS row, without inferring a human gamma-specific thermal sensor. PMID:12499492 is the verified intended clinical report, but only its abstract was recovered: it foregrounds an EIF2B5 case and the wider five-gene VWM syndrome. The exact gamma-specific provenance in that paper remains unresolved; the independent heat-response evidence does not authenticate an unobserved experiment in this citation and does not justify a wrong-paralog allegation.

Summary: Glucose-responsive regulation of the exchange factor is supported through the rat ortholog.

Reason: Current rat P70541 GO:0009749 IDA points to PMID:8567668. Its verified abstract reports rapid activation of whole eIF2B in isolated rat islets over glucose concentrations that stimulate insulin synthesis, with a nonmetabolizable analogue control. The ortholog transfer is retained as contextual regulation of translation, not human gamma glucose sensing or a gamma-specific assay. Complete donor Methods were not recovered.

Summary: The specific EIF2B3 attribution of the oligodendrocyte-development annotation remains unresolved.

Reason: The recovered PMID:15217090 Methods and Discussion describe five VWM autopsy patients: patients 1–4 carried EIF2B5 mutations and patient 5 an EIF2B2 mutation. Their oligodendrocyte density, proliferation and apoptotic observations are positive disease evidence, but the available operative material does not demonstrate an EIF2B3 perturbation or settle its specific developmental attribution. Shared complex dysfunction makes a gamma contribution plausible; neither an exact gamma experiment nor biological absence is inferred from these data.

Summary: The rat ortholog links eIF2B activity to the diabetic-muscle hormonal context.

Reason: Current rat P70541 GO:0043434 IDA cites PMID:8430778. Its verified abstract reports tissue-dependent eIF2B activity changes in diabetic rats and discusses NADPH/NADP+ and casein kinase II regulation. The existing ortholog response annotation is retained as a non-core physiological context. The accessible material does not establish a direct peptide-hormone-binding or sensing role for human gamma, and the complete donor Methods were not recovered.

Summary: Gamma-containing eIF2B promotes translation initiation through nucleotide exchange.

Reason: PMID:29599213 measures GDP exchange by recombinant human gamma-containing eIF2B and shows that assembly of the decameric factor enhances exchange. Gamma contributes structural organization alongside the catalytic epsilon subunit, helping regenerate initiation-competent eIF2. This is active participation in positive regulation of initiation, not merely a substrate requirement. ISRIB binding at the beta/delta interface and rodent cognitive effects are not assigned to gamma as separate activities.

Summary: The source supports eIF2B activation after T-cell stimulation but does not resolve a gamma-specific TCR-signaling role.

Reason: PMID:8626696 recovered Results measure whole-factor exchange after ionomycin/PMA stimulation of primary human lymphocytes, with similar PHA responses. Subunit abundance and RNA measurements use beta, while the proposed regulatory phosphorylation concerns epsilon and GSK3. GO:0050852 denotes the series of signals initiated by T-cell antigen-receptor cross-linking. The evidence positively supports stimulation-dependent translation control, but the available source does not establish which TCR signaling step EIF2B3 itself performs. Complete Experimental Procedures were unavailable; no negative gamma role is asserted.