EIF2S1 encodes eIF2alpha, the regulatory alpha subunit of the heterotrimeric translation initiation factor eIF2 (alpha, beta and gamma subunits). eIF2 binds GTP and initiator Met-tRNAi to form the ternary complex, which joins the 40S ribosomal subunit in the 43S/48S pre-initiation complex that scans mRNA for the start codon; after start-codon recognition eIF2-GDP is released and recycled to eIF2-GTP by the guanine nucleotide exchange factor eIF2B. eIF2 is a general initiation factor used by capped and IRES-driven mRNAs alike, not a cap- or IRES-binding factor. eIF2alpha is the convergence point of the integrated stress response: the kinases HRI (EIF2AK1), PKR (EIF2AK2), PERK (EIF2AK3) and GCN2 (EIF2AK4) phosphorylate its Ser52 (Ser51 in mature numbering) in response to heme deficiency and mitochondrial stress, viral dsRNA, ER stress and amino-acid starvation. Phosphorylated eIF2 binds and inhibits eIF2B, lowering ternary complex, attenuating global initiation and derepressing uORF-controlled mRNAs such as ATF4, and it triggers stress granule assembly. PP1 holophosphatases targeted by PPP1R15A (GADD34) and PPP1R15B (CReP) remove the phosphate. eIF2alpha is cytosolic; after HRI activation, phosphorylated eIF2alpha also accumulates on the mitochondrial surface, where it can trigger PARKIN-independent mitophagy.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0000423 mitophagy | IDA PMID:38340717 The HRI branch of the integrated stress response selectively... | KEEP AS NON CORE | Summary: Phosphorylated eIF2alpha generated by HRI relocalizes to the mitochondrial surface, and tethering phosphomimetic (S51D) but not WT or S51A eIF2alpha to mitochondria is sufficient to trigger mitophagy (Chakrabarty et al. 2024). Reason: Direct, well-controlled experimental support from a single recent study in K562 cells; phospho-eIF2alpha itself appears to be the signal that acts at the mitochondrion, so the gene product does some of the work. It is a newly described, secondary role of a translation initiation factor, mechanistically unresolved (how p-eIF2 recruits autophagy machinery is unknown), so it is kept as non-core. Supporting Evidence: PMID:38340717 Activation of the HRI branch results in mitochondrial localization of phosphorylated eukaryotic initiation factor 2, which we show is sufficient to induce mitophagy. PMID:38340717 Accompanying this mitochondrial localization, a substantial increase in mitophagy was measured in K562 cells expressing EIF2Ξ±S51D but not in cells expressing EIF2Ξ±WT or EIF2Ξ±S51A (Figure 5B). |
| GO:0003676 nucleic acid binding | IEA GO_REF:0000002 | MODIFY | Summary: InterPro S1-domain mapping to nucleic acid binding. The eIF2alpha N-terminal domain is an OB-fold S1 domain; mRNA interactome-capture studies place EIF2S1 among RNA-bound proteins. Reason: The S1 domain and interactome-capture data support RNA (not generic nucleic acid) binding, which the gene already carries (GO:0003723). The generic parent is refined to RNA binding, kept non-core because eIF2 activity is defined by Met-tRNAi delivery rather than by mRNA binding by the alpha subunit. Proposed replacements: RNA binding Supporting Evidence: file:human/EIF2S1/EIF2S1-uniprot.txt InterPro; IPR003029; S1_domain. PMID:22658674 We identify 860 proteins that qualify as RBPs by biochemical and statistical criteria |
| GO:0003723 RNA binding | HDA PMID:22658674 Insights into RNA biology from an atlas of mammalian mRNA-bi... | KEEP AS NON CORE | Summary: High-throughput mRNA interactome capture (UV crosslinking, oligo(dT) pull-down) in HeLa cells identified EIF2S1. Reason: Crosslinking to poly(A) RNA is consistent with eIF2alpha contacting mRNA within the scanning 48S complex, but the RNA-binding activity of the alpha subunit is not the defining function of eIF2; kept as non-core. Supporting Evidence: PMID:22658674 Employing two complementary protocols for covalent UV crosslinking of RBPs to RNA, we describe a systematic, unbiased, and comprehensive approach, termed "interactome capture," to define the mRNA interactome of proliferating human HeLa cells. |
| GO:0003723 RNA binding | HDA PMID:22681889 The mRNA-bound proteome and its global occupancy profile on ... | KEEP AS NON CORE | Summary: High-throughput mRNA-bound proteome (PAR-CL, oligo(dT)) in HEK293 cells identified EIF2S1. Reason: As for the other interactome-capture row; consistent with contact of mRNA within initiation complexes, not core. Supporting Evidence: PMID:22681889 We developed a photoreactive nucleotide-enhanced UV crosslinking and oligo(dT) purification approach to identify the mRNA-bound proteome using quantitative proteomics |
| GO:0003723 RNA binding | IEA GO_REF:0000002 | KEEP AS NON CORE | Summary: InterPro (TIF_2_asu, S1_IF2_alpha) mapping to RNA binding. Reason: Consistent with the S1 OB-fold domain and the interactome-capture data; true but peripheral to the core initiation-factor activity. Supporting Evidence: file:human/EIF2S1/EIF2S1-uniprot.txt InterPro; IPR044126; S1_IF2_alpha. |
| GO:0003743 translation initiation factor activity | IBA GO_REF:0000033 | ACCEPT | Summary: IBA from PAINT node PTN000063907 (eIF2alpha family), with experimental seeds including yeast SUI2, mouse Eif2s1 and human EIF2S1. Reason: eIF2 is the canonical initiation factor that forms the eIF2-GTP-Met-tRNAi ternary complex and delivers it to the 40S subunit; eIF2alpha is an essential subunit, conserved across eukaryotes. GO:0003743 is the correct level (eIF2 is neither cap- nor IRES-specific). Supporting Evidence: file:human/EIF2S1/EIF2S1-uniprot.txt Member of the eIF2 complex that functions in the early steps of protein synthesis by forming a ternary complex with GTP and initiator tRNA PMID:23063529 Together with GTP and initiator methionyl-tRNA, translation initiation factor eIF2 forms a ternary complex that binds the 40S ribosome and then scans an mRNA to select the AUG start codon for protein synthesis. |
| GO:0003743 translation initiation factor activity | IDA PMID:16289705 An efficient mammalian cell-free translation system suppleme... | ACCEPT | Summary: Supplementing HeLa cell-free extracts with purified eIF2 (with eIF2B) stimulated translation of capped, uncapped and EMCV-IRES mRNAs. Reason: The cell-free assay shows that eIF2 is a general (not cap- or IRES-specific) translation initiation factor. The cached record is abstract-only; the abstract supports this generic term, which is the core MF of eIF2 (contributed by the alpha subunit as part of the heterotrimer). 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:0003743 translation initiation factor activity | IEA GO_REF:0000120 | ACCEPT | Summary: Combined IEA (ortholog transfer from mouse Eif2s1 and InterPro TIF_2_asu). Reason: Agrees with the IBA and direct experimental rows; core activity of the eIF2 complex. Supporting Evidence: file:human/EIF2S1/EIF2S1-uniprot.txt InterPro; IPR011488; TIF_2_asu. PMID:23063529 Together with GTP and initiator methionyl-tRNA, translation initiation factor eIF2 forms a ternary complex that binds the 40S ribosome and then scans an mRNA to select the AUG start codon for protein synthesis. |
| GO:0003743 translation initiation factor activity | TAS PMID:2948954 Cloning and sequencing of complementary DNAs encoding the al... | ACCEPT | Summary: TAS from the cDNA cloning paper for eIF2alpha (Ernst et al. 1987), which characterizes the protein as the alpha subunit of initiation factor eIF-2. Reason: The paper identifies the cloned product as the alpha subunit of eIF-2, an established initiation factor; consistent with all other evidence. Supporting Evidence: PMID:2948954 The translation of hybrid-selected HeLa cell mRNA produces two proteins which are indistinguishable from authentic HeLa eIF-2 alpha and its phosphorylated form |
| GO:0005515 protein binding | IPI PMID:11500362 Eukaryotic initiation factor 2B: identification of multiple ... | REMOVE | Summary: Interaction with eIF2B epsilon (rat Q64350) reported in a study of eIF2B epsilon phosphorylation sites required for binding its substrate eIF2. Reason: Bare protein binding is uninformative. The eIF2-eIF2B interaction is the substrate relationship of the GEF; it is captured by the translation initiation factor activity and the regulation terms. Removal does not dispute the interaction. Supporting Evidence: PMID:11500362 They lie at the extreme C-terminus and are required for the interaction of eIF2Bepsilon with its substrate, eIF2, in vivo and for eIF2B activity in vitro. |
| GO:0005515 protein binding | IPI PMID:16288713 Interaction of recombinant human eIF2 subunits with eIF2B an... | REMOVE | Summary: Recombinant eIF2alpha interacts with the eIF2alpha kinase PKR (EIF2AK2). Reason: Uninformative protein binding; eIF2alpha is the kinase substrate. The relationship is better captured on the kinase (eIF2alpha kinase activity) than as a binding function of the substrate. Supporting Evidence: PMID:16288713 The heterotrimeric eukaryotic initiation factor 2 (eIF2) plays a critical role in the mechanics and regulation of protein synthesis. |
| GO:0005515 protein binding | IPI PMID:16288713 Interaction of recombinant human eIF2 subunits with eIF2B an... | REMOVE | Summary: eIF2alpha interacts with eIF2beta (EIF2S2) in recombinant subunit assays. Reason: Uninformative protein binding; intra-complex subunit contact is captured by the eIF2 complex (GO:0005850) annotation. Supporting Evidence: PMID:16288713 the purified baculovirus-expressed recombinant human eIF2 subunits used in these studies reveal that the alpha- and beta-subunits interact with each other |
| GO:0005515 protein binding | IPI PMID:16288713 Interaction of recombinant human eIF2 subunits with eIF2B an... | REMOVE | Summary: Interaction with eIF2gamma (EIF2S3). Reason: Uninformative protein binding; subunit membership is captured by GO:0005850. Supporting Evidence: PMID:16288713 The heterotrimeric eukaryotic initiation factor 2 (eIF2) plays a critical role in the mechanics and regulation of protein synthesis. |
| GO:0005515 protein binding | IPI PMID:16288713 Interaction of recombinant human eIF2 subunits with eIF2B an... | REMOVE | Summary: Interaction with mouse PERK (Eif2ak3), its kinase. Reason: Uninformative protein binding; kinase-substrate interaction. Supporting Evidence: PMID:16288713 PERK, an eIF2alpha kinase, is found to interact with wt and mutants of eIF2alpha in which the serine 51 or 48 residue is replaced by alanine or aspartic acid thereby suggesting that the phosphorylation site in the substrate is not important for interaction. |
| GO:0005515 protein binding | IPI PMID:16932749 p97/DAP5 is a ribosome-associated factor that facilitates pr... | REMOVE | Summary: Co-purification with EIF2S2 in a study of p97/DAP5 ribosome association. Reason: Uninformative protein binding; eIF2 subunit contacts are captured by the complex annotation. Supporting Evidence: file:human/EIF2S1/EIF2S1-uniprot.txt Eukaryotic translation initiation factor 2 eIF2 is a heterotrimeric complex composed of an alpha (EIF2S1), a beta (EIF2S2) and a gamma (EIF2S3) chain |
| GO:0005515 protein binding | IPI PMID:17894550 The N-terminal region of ABC50 interacts with eukaryotic ini... | REMOVE | Summary: eIF2 interacts with the N-terminal region of ABC50 (ABCF1). Reason: Uninformative protein binding; the cited study maps the ABC50-eIF2 interaction on ABC50, not a function of eIF2alpha. Supporting Evidence: PMID:17894550 Here, we establish that the interaction of ABC50 with eIF2 involves features in the N-terminal domain of ABC50 |
| GO:0005515 protein binding | IPI PMID:17894550 The N-terminal region of ABC50 interacts with eukaryotic ini... | REMOVE | Summary: Same ABC50 interaction (ABCF1 isoform 2). Reason: Uninformative protein binding, as for the ABCF1 canonical isoform row. Supporting Evidence: PMID:17894550 Here, we establish that the interaction of ABC50 with eIF2 involves features in the N-terminal domain of ABC50 |
| GO:0005515 protein binding | IPI PMID:18596238 The DEAD-box RNA helicase DDX3 associates with export messen... | REMOVE | Summary: RNA-independent interaction with DDX3X. Reason: Uninformative protein binding; reflects DDX3X association with initiation complexes. Supporting Evidence: file:human/EIF2S1/EIF2S1-uniprot.txt Interacts with DDX3X in an RNA-independent manner (PubMed:18596238). |
| GO:0005515 protein binding | IPI PMID:18971339 Protein kinase PKR mutants resistant to the poxvirus pseudos... | REMOVE | Summary: Interaction with PKR (EIF2AK2) in a study of PKR mutants resistant to the poxvirus K3L pseudosubstrate. Reason: Uninformative protein binding; kinase-substrate interaction. Supporting Evidence: PMID:18971339 Protein kinase PKR mutants resistant to the poxvirus pseudosubstrate K3L protein. |
| GO:0005515 protein binding | IPI PMID:22323517 The DEAD-box helicase DDX3 supports the assembly of function... | REMOVE | Summary: Interaction with DDX3X, which associates with pre-initiation complex components. Reason: Uninformative protein binding. Supporting Evidence: PMID:22323517 DDX3 was found to interact in an RNA-independent manner with defined components of the translational pre-initiation complex |
| GO:0005515 protein binding | IPI PMID:25393282 TBL2 is a novel PERK-binding protein that modulates stress-s... | REMOVE | Summary: Interaction with TBL2, a PERK-binding protein. Reason: Uninformative protein binding; no function of eIF2alpha is identified. Supporting Evidence: PMID:25393282 TBL2 is a novel PERK-binding protein that modulates stress-signaling and cell survival during endoplasmic reticulum stress. |
| GO:0005515 protein binding | IPI PMID:26095357 Structural and Functional Analysis of the GADD34:PP1 eIF2Ξ± P... | REMOVE | Summary: Interaction with PP1 catalytic subunit PPP1CA, as substrate of the GADD34-PP1 holophosphatase. Reason: Uninformative protein binding; eIF2alpha is the substrate of the PP1-PPP1R15 phosphatase, and GADD34 acts as the scaffold recruiting it. Supporting Evidence: PMID:26095357 The data highlight independent interactions of PP1 and eIF2Ξ± with GADD34, demonstrating that GADD34 functions as a scaffold both in vitro and in cells. |
| GO:0005515 protein binding | IPI PMID:28514442 Architecture of the human interactome defines protein commun... | REMOVE | Summary: Binary/co-complex interactome detection of EIF2S2. Reason: Uninformative protein binding; captured by complex membership. Supporting Evidence: file:human/EIF2S1/EIF2S1-uniprot.txt Eukaryotic translation initiation factor 2 eIF2 is a heterotrimeric complex composed of an alpha (EIF2S1), a beta (EIF2S2) and a gamma (EIF2S3) chain |
| GO:0005515 protein binding | IPI PMID:29599213 Structure of the nucleotide exchange factor eIF2B reveals me... | REMOVE | Summary: eIF2 subunit interaction (EIF2S2) in the eIF2B structural study. Reason: Uninformative protein binding; captured by complex membership. Supporting Evidence: file:human/EIF2S1/EIF2S1-uniprot.txt Eukaryotic translation initiation factor 2 eIF2 is a heterotrimeric complex composed of an alpha (EIF2S1), a beta (EIF2S2) and a gamma (EIF2S3) chain |
| GO:0005515 protein binding | IPI PMID:29599213 Structure of the nucleotide exchange factor eIF2B reveals me... | REMOVE | Summary: eIF2 subunit interaction (EIF2S3) in the eIF2B structural study. Reason: Uninformative protein binding; captured by complex membership. Supporting Evidence: file:human/EIF2S1/EIF2S1-uniprot.txt Eukaryotic translation initiation factor 2 eIF2 is a heterotrimeric complex composed of an alpha (EIF2S1), a beta (EIF2S2) and a gamma (EIF2S3) chain |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | REMOVE | Summary: High-throughput binary interactome (HuRI) hit with ACTN1. Reason: Uninformative protein binding from a yeast two-hybrid screen; no functional context. Supporting Evidence: PMID:32296183 A reference map of the human binary protein interactome. |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | REMOVE | Summary: HuRI binary interactome hit with VAC14. Reason: Uninformative protein binding from a high-throughput screen. Supporting Evidence: PMID:32296183 A reference map of the human binary protein interactome. |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | REMOVE | Summary: HuRI binary interactome hit with PRMT7. Reason: Uninformative protein binding from a high-throughput screen. Supporting Evidence: PMID:32296183 A reference map of the human binary protein interactome. |
| GO:0005515 protein binding | IPI PMID:33961781 Dual proteome-scale networks reveal cell-specific remodeling... | REMOVE | Summary: Proteome-scale co-complex interaction with EIF2S2. Reason: Uninformative protein binding; captured by complex membership. Supporting Evidence: file:human/EIF2S1/EIF2S1-uniprot.txt Eukaryotic translation initiation factor 2 eIF2 is a heterotrimeric complex composed of an alpha (EIF2S1), a beta (EIF2S2) and a gamma (EIF2S3) chain |
| GO:0005515 protein binding | IPI PMID:33961781 Dual proteome-scale networks reveal cell-specific remodeling... | REMOVE | Summary: Proteome-scale co-complex interaction with EIF2S3. Reason: Uninformative protein binding; captured by complex membership. Supporting Evidence: file:human/EIF2S1/EIF2S1-uniprot.txt Eukaryotic translation initiation factor 2 eIF2 is a heterotrimeric complex composed of an alpha (EIF2S1), a beta (EIF2S2) and a gamma (EIF2S3) chain |
| GO:0005515 protein binding | IPI PMID:33961781 Dual proteome-scale networks reveal cell-specific remodeling... | REMOVE | Summary: Proteome-scale interaction with PRMT7. Reason: Uninformative protein binding from a high-throughput screen. Supporting Evidence: PMID:33961781 Dual proteome-scale networks reveal cell-specific remodeling of the human interactome. |
| GO:0005515 protein binding | IPI PMID:35271311 OpenCell: Endogenous tagging for the cartography of human ce... | REMOVE | Summary: OpenCell endogenous-tag interaction with EIF2S3. Reason: Uninformative protein binding; captured by complex membership. Supporting Evidence: file:human/EIF2S1/EIF2S1-uniprot.txt Eukaryotic translation initiation factor 2 eIF2 is a heterotrimeric complex composed of an alpha (EIF2S1), a beta (EIF2S2) and a gamma (EIF2S3) chain |
| GO:0005515 protein binding | IPI PMID:37507029 Binding of human Cdc123 to eIF2Ξ³. | REMOVE | Summary: Co-purification with EIF2S3 in a study of CDC123 binding to eIF2gamma. Reason: Uninformative protein binding; captured by complex membership (CDC123 promotes eIF2 assembly). Supporting Evidence: file:human/EIF2S1/EIF2S1-uniprot.txt Eukaryotic translation initiation factor 2 eIF2 is a heterotrimeric complex composed of an alpha (EIF2S1), a beta (EIF2S2) and a gamma (EIF2S3) chain |
| GO:0005515 protein binding | IPI PMID:9431994 Homologous regions of the alpha subunit of eukaryotic transl... | REMOVE | Summary: eIF2alpha binds the C-terminal catalytic domain of PKR in vitro. Reason: Uninformative protein binding; kinase-substrate interaction. Supporting Evidence: PMID:9431994 The data presented here demonstrate that the natural substrate, eIF2alpha, also binds to PKR in vitro and interacts with the same or an overlapping domain within PKR. |
| GO:0005634 nucleus | IEA GO_REF:0000107 | MARK AS OVER ANNOTATED | Summary: Ensembl ortholog transfer of nucleus from mouse Eif2s1. Reason: eIF2 acts in cytoplasmic translation initiation; the curated human record lists cytoplasm, cytosol, stress granule and mitochondrion but not nucleus. A nuclear p-eIF2alpha immunofluorescence signal was noted (and removed from analysis) in one study, but no function of eIF2alpha in the nucleus is established. Supporting Evidence: file:human/EIF2S1/EIF2S1-uniprot.txt SUBCELLULAR LOCATION: Cytoplasm, Stress granule PMID:38340717 Before analyzing the co-localization between TOM20 and p-EIF2Ξ±, the nuclear signal for p-EIF2Ξ± was removed post-imaging using the DAPI channel. |
| GO:0005737 cytoplasm | IEA GO_REF:0000107 | MODIFY | Summary: Ensembl ortholog transfer of cytoplasm from mouse. Reason: Correct but general; eIF2alpha functions in the cytosol, which the gene already carries by IDA (HPA) and Reactome TAS. Proposed replacements: cytosol Supporting Evidence: PMID:38340717 whereas Tg treatment resulted in p-EIF2Ξ± localization almost exclusively in the cytosolic fraction (Figure 4A). |
| GO:0005737 cytoplasm | ISS GO_REF:0000024 | MODIFY | Summary: ISS from mouse Eif2s1 (is_active_in cytoplasm). Reason: Correct but general; translation initiation by eIF2 is cytosolic, as captured by the existing cytosol rows. Proposed replacements: cytosol Supporting Evidence: PMID:38340717 whereas Tg treatment resulted in p-EIF2Ξ± localization almost exclusively in the cytosolic fraction (Figure 4A). |
| GO:0005739 mitochondrion | IDA PMID:38340717 The HRI branch of the integrated stress response selectively... | KEEP AS NON CORE | Summary: Biochemical fractionation and TOM20 co-immunostaining show phospho-eIF2alpha accumulating on mitochondria after HRI activation (DFP), with an ER marker excluding ER contamination of the fraction. Reason: Direct evidence (fractionation checked with an ER marker, plus imaging) for stress-induced recruitment of p-eIF2alpha to the mitochondrion; peripheral to the core cytosolic initiation role. Per the organelle policy the root term is kept and no sub-compartment is added - this is transient recruitment to the organelle surface, not an outer-membrane location. Supporting Evidence: PMID:38340717 However, DFP treatment resulted in notable accumulation of p-EIF2Ξ± in the mitochondrial fraction, whereas Tg treatment resulted in p-EIF2Ξ± localization almost exclusively in the cytosolic fraction (Figure 4A). PMID:38340717 Analysis of the subcellular fractions with an ER marker showed no evidence of ER enrichment of p-EIF2Ξ± upon DFP treatment (Figure S4C). |
| GO:0005739 mitochondrion | IEA GO_REF:0000044 | KEEP AS NON CORE | Summary: UniProt subcellular-location keyword mapping (Mitochondrion), itself derived from PMID:38340717. Reason: The keyword rests on the experimental HRI/mitophagy study (checked; see the IDA row). The organelle claim holds for stress-induced p-eIF2alpha; non-core. Supporting Evidence: file:human/EIF2S1/EIF2S1-uniprot.txt Relocalizes to the surface of mitochondria in response to mitochondrial damage and phosphorylation by EIF2AK1/HRI (PubMed:38340717). |
| GO:0005829 cytosol | IDA GO_REF:0000052 | ACCEPT | Summary: Human Protein Atlas immunofluorescence localizes EIF2S1 to the cytosol. Reason: eIF2 functions in cytosolic translation initiation; this is the core location. Supporting Evidence: PMID:38340717 whereas Tg treatment resulted in p-EIF2Ξ± localization almost exclusively in the cytosolic fraction (Figure 4A). |
| GO:0005829 cytosol | IEA GO_REF:0000044 | ACCEPT | Summary: Cytosol (UniProt subcellular-location keyword or Reactome TAS for eIF2-containing reactions - ternary complex formation, 43S/48S assembly, eIF2B recycling, eIF2alpha phosphorylation by the ISR kinases). Reason: Consistent with the cytosolic site of eIF2 function and the HPA IDA row. Supporting Evidence: file:human/EIF2S1/EIF2S1-uniprot.txt Cytoplasm, cytosol |
| GO:0005829 cytosol | TAS Reactome:R-HSA-156808 | ACCEPT | Summary: Cytosol (UniProt subcellular-location keyword or Reactome TAS for eIF2-containing reactions - ternary complex formation, 43S/48S assembly, eIF2B recycling, eIF2alpha phosphorylation by the ISR kinases). Reason: Consistent with the cytosolic site of eIF2 function and the HPA IDA row. Supporting Evidence: file:human/EIF2S1/EIF2S1-uniprot.txt Cytoplasm, cytosol |
| GO:0005829 cytosol | TAS Reactome:R-HSA-156823 | ACCEPT | Summary: Cytosol (UniProt subcellular-location keyword or Reactome TAS for eIF2-containing reactions - ternary complex formation, 43S/48S assembly, eIF2B recycling, eIF2alpha phosphorylation by the ISR kinases). Reason: Consistent with the cytosolic site of eIF2 function and the HPA IDA row. Supporting Evidence: file:human/EIF2S1/EIF2S1-uniprot.txt Cytoplasm, cytosol |
| GO:0005829 cytosol | TAS Reactome:R-HSA-157849 | ACCEPT | Summary: Cytosol (UniProt subcellular-location keyword or Reactome TAS for eIF2-containing reactions - ternary complex formation, 43S/48S assembly, eIF2B recycling, eIF2alpha phosphorylation by the ISR kinases). Reason: Consistent with the cytosolic site of eIF2 function and the HPA IDA row. Supporting Evidence: file:human/EIF2S1/EIF2S1-uniprot.txt Cytoplasm, cytosol |
| GO:0005829 cytosol | TAS Reactome:R-HSA-381111 | ACCEPT | Summary: Cytosol (UniProt subcellular-location keyword or Reactome TAS for eIF2-containing reactions - ternary complex formation, 43S/48S assembly, eIF2B recycling, eIF2alpha phosphorylation by the ISR kinases). Reason: Consistent with the cytosolic site of eIF2 function and the HPA IDA row. Supporting Evidence: file:human/EIF2S1/EIF2S1-uniprot.txt Cytoplasm, cytosol |
| GO:0005829 cytosol | TAS Reactome:R-HSA-5227009 | ACCEPT | Summary: Cytosol (UniProt subcellular-location keyword or Reactome TAS for eIF2-containing reactions - ternary complex formation, 43S/48S assembly, eIF2B recycling, eIF2alpha phosphorylation by the ISR kinases). Reason: Consistent with the cytosolic site of eIF2 function and the HPA IDA row. Supporting Evidence: file:human/EIF2S1/EIF2S1-uniprot.txt Cytoplasm, cytosol |
| GO:0005829 cytosol | TAS Reactome:R-HSA-72619 | ACCEPT | Summary: Cytosol (UniProt subcellular-location keyword or Reactome TAS for eIF2-containing reactions - ternary complex formation, 43S/48S assembly, eIF2B recycling, eIF2alpha phosphorylation by the ISR kinases). Reason: Consistent with the cytosolic site of eIF2 function and the HPA IDA row. Supporting Evidence: file:human/EIF2S1/EIF2S1-uniprot.txt Cytoplasm, cytosol |
| GO:0005829 cytosol | TAS Reactome:R-HSA-72621 | ACCEPT | Summary: Cytosol (UniProt subcellular-location keyword or Reactome TAS for eIF2-containing reactions - ternary complex formation, 43S/48S assembly, eIF2B recycling, eIF2alpha phosphorylation by the ISR kinases). Reason: Consistent with the cytosolic site of eIF2 function and the HPA IDA row. Supporting Evidence: file:human/EIF2S1/EIF2S1-uniprot.txt Cytoplasm, cytosol |
| GO:0005829 cytosol | TAS Reactome:R-HSA-72663 | ACCEPT | Summary: Cytosol (UniProt subcellular-location keyword or Reactome TAS for eIF2-containing reactions - ternary complex formation, 43S/48S assembly, eIF2B recycling, eIF2alpha phosphorylation by the ISR kinases). Reason: Consistent with the cytosolic site of eIF2 function and the HPA IDA row. Supporting Evidence: file:human/EIF2S1/EIF2S1-uniprot.txt Cytoplasm, cytosol |
| GO:0005829 cytosol | TAS Reactome:R-HSA-72669 | ACCEPT | Summary: Cytosol (UniProt subcellular-location keyword or Reactome TAS for eIF2-containing reactions - ternary complex formation, 43S/48S assembly, eIF2B recycling, eIF2alpha phosphorylation by the ISR kinases). Reason: Consistent with the cytosolic site of eIF2 function and the HPA IDA row. Supporting Evidence: file:human/EIF2S1/EIF2S1-uniprot.txt Cytoplasm, cytosol |
| GO:0005829 cytosol | TAS Reactome:R-HSA-72670 | ACCEPT | Summary: Cytosol (UniProt subcellular-location keyword or Reactome TAS for eIF2-containing reactions - ternary complex formation, 43S/48S assembly, eIF2B recycling, eIF2alpha phosphorylation by the ISR kinases). Reason: Consistent with the cytosolic site of eIF2 function and the HPA IDA row. Supporting Evidence: file:human/EIF2S1/EIF2S1-uniprot.txt Cytoplasm, cytosol |
| GO:0005829 cytosol | TAS Reactome:R-HSA-72691 | ACCEPT | Summary: Cytosol (UniProt subcellular-location keyword or Reactome TAS for eIF2-containing reactions - ternary complex formation, 43S/48S assembly, eIF2B recycling, eIF2alpha phosphorylation by the ISR kinases). Reason: Consistent with the cytosolic site of eIF2 function and the HPA IDA row. Supporting Evidence: file:human/EIF2S1/EIF2S1-uniprot.txt Cytoplasm, cytosol |
| GO:0005829 cytosol | TAS Reactome:R-HSA-72697 | ACCEPT | Summary: Cytosol (UniProt subcellular-location keyword or Reactome TAS for eIF2-containing reactions - ternary complex formation, 43S/48S assembly, eIF2B recycling, eIF2alpha phosphorylation by the ISR kinases). Reason: Consistent with the cytosolic site of eIF2 function and the HPA IDA row. Supporting Evidence: file:human/EIF2S1/EIF2S1-uniprot.txt Cytoplasm, cytosol |
| GO:0005829 cytosol | TAS Reactome:R-HSA-72722 | ACCEPT | Summary: Cytosol (UniProt subcellular-location keyword or Reactome TAS for eIF2-containing reactions - ternary complex formation, 43S/48S assembly, eIF2B recycling, eIF2alpha phosphorylation by the ISR kinases). Reason: Consistent with the cytosolic site of eIF2 function and the HPA IDA row. Supporting Evidence: file:human/EIF2S1/EIF2S1-uniprot.txt Cytoplasm, cytosol |
| GO:0005829 cytosol | TAS Reactome:R-HSA-9835885 | ACCEPT | Summary: Cytosol (UniProt subcellular-location keyword or Reactome TAS for eIF2-containing reactions - ternary complex formation, 43S/48S assembly, eIF2B recycling, eIF2alpha phosphorylation by the ISR kinases). Reason: Consistent with the cytosolic site of eIF2 function and the HPA IDA row. Supporting Evidence: file:human/EIF2S1/EIF2S1-uniprot.txt Cytoplasm, cytosol |
| GO:0005829 cytosol | TAS Reactome:R-HSA-9840415 | ACCEPT | Summary: Cytosol (UniProt subcellular-location keyword or Reactome TAS for eIF2-containing reactions - ternary complex formation, 43S/48S assembly, eIF2B recycling, eIF2alpha phosphorylation by the ISR kinases). Reason: Consistent with the cytosolic site of eIF2 function and the HPA IDA row. Supporting Evidence: file:human/EIF2S1/EIF2S1-uniprot.txt Cytoplasm, cytosol |
| GO:0005850 eukaryotic translation initiation factor 2 complex | IBA GO_REF:0000033 | ACCEPT | Summary: IBA from PAINT node PTN000063908 for the eIF2 complex. Reason: EIF2S1 is the alpha subunit of the eIF2 heterotrimer in all eukaryotes. Supporting Evidence: file:human/EIF2S1/EIF2S1-uniprot.txt Eukaryotic translation initiation factor 2 eIF2 is a heterotrimeric complex composed of an alpha (EIF2S1), a beta (EIF2S2) and a gamma (EIF2S3) chain |
| GO:0005850 eukaryotic translation initiation factor 2 complex | IDA PMID:23063529 eIF2Ξ³ mutation that disrupts eIF2 complex integrity links in... | ACCEPT | Summary: eIF2 complex integrity assays in human cells (Borck et al. 2012). Reason: Direct evidence that EIF2S1 is part of the eIF2 heterotrimer. Supporting Evidence: PMID:23063529 the core subunit of the heterotrimeric eIF2 complex |
| GO:0005850 eukaryotic translation initiation factor 2 complex | IEA GO_REF:0000107 | ACCEPT | Summary: Ensembl ortholog transfer from rat Eif2s1. Reason: Consistent with direct human evidence. Supporting Evidence: file:human/EIF2S1/EIF2S1-uniprot.txt Eukaryotic translation initiation factor 2 eIF2 is a heterotrimeric complex composed of an alpha (EIF2S1), a beta (EIF2S2) and a gamma (EIF2S3) chain |
| GO:0005850 eukaryotic translation initiation factor 2 complex | IPI PMID:23063529 eIF2Ξ³ mutation that disrupts eIF2 complex integrity links in... | ACCEPT | Summary: IPI for eIF2 complex membership (Borck et al. 2012). Reason: Co-purification of eIF2 subunits supports membership in the heterotrimer. Supporting Evidence: PMID:23063529 the core subunit of the heterotrimeric eIF2 complex |
| GO:0005850 eukaryotic translation initiation factor 2 complex | IPI PMID:31836389 Suppression of MEHMO Syndrome Mutation in eIF2 by Small Mole... | ACCEPT | Summary: IPI with EIF2S3 in the MEHMO/ISRIB study (Young-Baird et al. 2020), which examined CDC123-promoted eIF2 assembly. Reason: Supports EIF2S1 incorporation into eIF2. Supporting Evidence: PMID:31836389 we show that a mutation at the C terminus of eIF2Ξ³ impairs CDC123 promotion of eIF2 complex formation and decreases the level of eIF2-GTP-Met-tRNAiMet ternary complexes. |
| GO:0006413 translational initiation | IBA GO_REF:0000033 | MODIFY | Summary: IBA translational initiation from PTN000063907. Reason: Correct but general. eIF2 acts in cytoplasmic (not mitochondrial) translation initiation; GO:0002183 cytoplasmic translational initiation is the precise is_a child. The phylogenetic claim itself (eIF2alpha is an initiation factor throughout eukaryotes) is sound. Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: GRANULARITY MISMATCH Sources checked: PANTHER:PTN000063907 SUPPORTS TRANSFER The eIF2alpha node correctly places initiation-factor function at the base of the family; the row is only less specific than cytoplasmic translational initiation. Proposed replacements: cytoplasmic translational initiation Supporting Evidence: PMID:23063529 Together with GTP and initiator methionyl-tRNA, translation initiation factor eIF2 forms a ternary complex that binds the 40S ribosome and then scans an mRNA to select the AUG start codon for protein synthesis. |
| GO:0006413 translational initiation | IDA PMID:16289705 An efficient mammalian cell-free translation system suppleme... | MODIFY | Summary: Cell-free translation stimulated by eIF2. Reason: Correct but general; the assay is cytoplasmic (HeLa extract) mRNA translation, so GO:0002183 cytoplasmic translational initiation is the precise term. 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. |
| GO:0006413 translational initiation | IEA GO_REF:0000107 | MODIFY | Summary: Ensembl ortholog transfer from mouse. Reason: Correct but general; replaced with cytoplasmic translational initiation, as for the IBA and IDA rows. Proposed replacements: cytoplasmic translational initiation Supporting Evidence: file:human/EIF2S1/EIF2S1-uniprot.txt Member of the eIF2 complex that functions in the early steps of protein synthesis by forming a ternary complex with GTP and initiator tRNA |
| GO:0006446 regulation of translational initiation | NAS PMID:18639529 Intersubunit and interprotein interactions of alpha- and bet... | MODIFY | Summary: ComplexPortal NAS from a study of eIF2 subunit interactions and the effect of phosphorylation. Reason: Correct but general. Phosphorylated eIF2alpha binds and inhibits eIF2B, lowering ternary complex and initiation under stress; the more precise term GO:0032057 negative regulation of translational initiation in response to stress is already carried by the gene (ISS/IEA). GO:0010998 (regulation of translational initiation by eIF2 alpha phosphorylation) was not chosen because it is_a protein phosphorylation, a process performed by the kinases. Proposed replacements: negative regulation of translational initiation in response to stress Supporting Evidence: PMID:18639529 These findings suggest that subunits of mammalian eIF2 interact with each other and the beta-subunit plays a critical role both in the regulation and function of eIF2. file:human/EIF2S1/EIF2S1-uniprot.txt Activity is regulated by phosphorylation at Ser-49 and Ser-52, which stabilizes the eIF2/GDP/eIF2B complex and prevents the eIF2B-mediated exchange of GDP for GTP |
| GO:0010494 cytoplasmic stress granule | IEA GO_REF:0000120 | KEEP AS NON CORE | Summary: Combined IEA (mouse ortholog and UniProt SubCell keyword) for stress granule. Reason: The human entry carries stress granule only by similarity to mouse (colocalization with NANOS3). eIF2alpha phosphorylation initiates stress granule assembly, and stalled initiation complexes are the granule nucleus, so presence is plausible; it is peripheral to the core function. Supporting Evidence: file:human/EIF2S1/EIF2S1-uniprot.txt Colocalizes with NANOS3 in the stress granules (By similarity). |
| GO:0010494 cytoplasmic stress granule | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: ISS from mouse Eif2s1 for stress granule. Reason: As for the IEA row; plausible, peripheral. Supporting Evidence: file:human/EIF2S1/EIF2S1-uniprot.txt Colocalizes with NANOS3 in the stress granules (By similarity). |
| GO:0016020 membrane | HDA PMID:19946888 Defining the membrane proteome of NK cells. | MARK AS OVER ANNOTATED | Summary: NK-cell membrane proteomics identified EIF2S1. Reason: eIF2alpha is a soluble cytosolic protein with no transmembrane segment; the study itself notes that most non-integral hits are transiently membrane-associated. Not an informative localization. Supporting Evidence: PMID:19946888 The remaining species were largely involved in cellular processes and molecular functions that could be predicted to be transiently associated with membranes. |
| GO:0032057 negative regulation of translational initiation in response to stress | IEA GO_REF:0000107 | ACCEPT | Summary: Ensembl ortholog transfer from mouse. Reason: Phosphorylation of eIF2alpha by any of the four ISR kinases converts eIF2 into an inhibitor of eIF2B, lowering ternary complex and globally attenuating initiation; this is the central regulatory role of EIF2S1. Supporting Evidence: file:human/EIF2S1/EIF2S1-uniprot.txt Activity is regulated by phosphorylation at Ser-49 and Ser-52, which stabilizes the eIF2/GDP/eIF2B complex and prevents the eIF2B-mediated exchange of GDP for GTP PMID:10613902 Phosphorylation of eIF-2Ξ± increases the affinity of eIF-2 for eIF-2B, and prevents the exchange of GDP for GTP, thereby inhibiting the formation of preinitiation complexes. |
| GO:0032057 negative regulation of translational initiation in response to stress | ISS GO_REF:0000024 | ACCEPT | Summary: ISS from mouse Eif2s1. Reason: As for the IEA row; core regulatory role. Supporting Evidence: PMID:10613902 Phosphorylation of eIF-2Ξ± increases the affinity of eIF-2 for eIF-2B, and prevents the exchange of GDP for GTP, thereby inhibiting the formation of preinitiation complexes. |
| GO:0033290 eukaryotic 48S preinitiation complex | IBA GO_REF:0000033 | ACCEPT | Summary: IBA for the 48S preinitiation complex. Reason: The eIF2 ternary complex is a component of the 43S/48S pre-initiation complex that scans mRNA for the start codon. Supporting Evidence: PMID:23063529 Together with GTP and initiator methionyl-tRNA, translation initiation factor eIF2 forms a ternary complex that binds the 40S ribosome and then scans an mRNA to select the AUG start codon for protein synthesis. |
| GO:0034063 cytoplasmic stress granule assembly | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Ensembl ortholog transfer of stress granule assembly from mouse. Reason: Phosphomimetic eIF2alpha S51D is sufficient, and non-phosphorylatable S51A blocks, stress granule assembly; phospho-eIF2alpha is the initiating event. Its effect is through translational arrest (TIA-1/TIAR act downstream), so it is a downstream consequence of the core role and is kept as non-core. Supporting Evidence: PMID:10613902 A phosphomimetic eIF-2alpha mutant (S51D) induces the assembly of SGs, whereas a nonphosphorylatable eIF-2alpha mutant (S51A) prevents the assembly of SGs. |
| GO:0034063 cytoplasmic stress granule assembly | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: ISS from mouse. Reason: As for the IEA row. Supporting Evidence: PMID:10613902 As we have now identified eIF-2Ξ± phosphorylation as the molecular event that initiates SG formation |
| GO:0034198 cellular response to amino acid starvation | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Ensembl ortholog transfer (response to amino acid starvation). Reason: eIF2alpha is phosphorylated by GCN2 during amino-acid starvation; true, but one of several stress inputs converging on the core ISR role. Supporting Evidence: file:human/EIF2S1/EIF2S1-uniprot.txt Phosphorylation on Ser-52 by the EIF2AK4/GCN2 protein kinase occurs in response to amino acid starvation and UV irradiation (By similarity). |
| GO:0034198 cellular response to amino acid starvation | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: ISS from mouse (response to amino acid starvation). Reason: As for the IEA row. Supporting Evidence: file:human/EIF2S1/EIF2S1-uniprot.txt Phosphorylation on Ser-52 by the EIF2AK4/GCN2 protein kinase occurs in response to amino acid starvation and UV irradiation (By similarity). |
| GO:0034599 cellular response to oxidative stress | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Ensembl ortholog transfer (response to oxidative stress). Reason: Oxidative stress (e.g. arsenite) triggers eIF2alpha phosphorylation through HRI; one of many stress inputs to the ISR. Supporting Evidence: file:human/EIF2S1/EIF2S1-uniprot.txt EIF2S1/eIF2-alpha is a key component of the integrated stress response (ISR), required for adaptation to various stress |
| GO:0034599 cellular response to oxidative stress | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: ISS from mouse (response to oxidative stress). Reason: As for the IEA row. Supporting Evidence: file:human/EIF2S1/EIF2S1-uniprot.txt EIF2S1/eIF2-alpha is a key component of the integrated stress response (ISR), required for adaptation to various stress |
| GO:0034605 cellular response to heat | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Ensembl ortholog transfer from rat (response to heat). Reason: Heat shock causes eIF2alpha phosphorylation and stress granule assembly; a stress input to the ISR, non-core. Supporting Evidence: PMID:10613902 The general translational arrest that accompanies environmental stress is initiated by the phosphorylation of eIF-2Ξ± |
| GO:0034644 cellular response to UV | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Ensembl ortholog transfer (response to UV). Reason: UV irradiation induces GCN2-dependent eIF2alpha phosphorylation; a stress input, non-core. Supporting Evidence: file:human/EIF2S1/EIF2S1-uniprot.txt Phosphorylation on Ser-52 by the EIF2AK4/GCN2 protein kinase occurs in response to amino acid starvation and UV irradiation (By similarity). |
| GO:0034644 cellular response to UV | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: ISS from mouse (response to UV). Reason: As for the IEA row. Supporting Evidence: file:human/EIF2S1/EIF2S1-uniprot.txt Phosphorylation on Ser-52 by the EIF2AK4/GCN2 protein kinase occurs in response to amino acid starvation and UV irradiation (By similarity). |
| GO:0034976 response to endoplasmic reticulum stress | IDA PMID:33384352 QRICH1 dictates the outcome of ER stress through transcripti... | KEEP AS NON CORE | Summary: QRICH1 CRISPR-screen study identifying QRICH1 as an effector of the PERK-eIF2alpha axis (abstract-only cache). Reason: eIF2alpha phosphorylation by PERK is a central output of ER stress; the broad response term is true. The more precise PERK-mediated UPR term is accepted separately; this broad response term is kept as non-core. Deferring to the curator for the full-text experiment. Supporting Evidence: PMID:33384352 We identified QRICH1 as a key effector of the PERK-eIF2Ξ± axis of the UPR. |
| GO:0034976 response to endoplasmic reticulum stress | IEA GO_REF:0000120 | KEEP AS NON CORE | Summary: Combined IEA (ARBA and mouse ortholog) for response to ER stress. Reason: True (PERK phosphorylates eIF2alpha under ER stress) but broad; kept non-core beside the accepted PERK-mediated UPR rows. Supporting Evidence: file:human/EIF2S1/EIF2S1-uniprot.txt Phosphorylation at Ser-52 by the EIF2AK3/PERK protein kinase occurs in response to the unfolded protein response (PubMed:10026192). |
| GO:0034976 response to endoplasmic reticulum stress | IMP PMID:18508033 GSK3beta and endoplasmic reticulum stress mediate rotenone-i... | KEEP AS NON CORE | Summary: eIF2alpha siRNA reduced rotenone-induced ER-stress-associated death of SK-N-MC cells. Reason: Knockdown evidence links eIF2alpha to the cellular outcome of rotenone-induced ER stress; true, but a broad, context-specific response term. Abstract-only; deferring to the curator on the experiment. Supporting Evidence: PMID:18508033 Rotenone also induced endoplasmic reticulum (ER) stress which was evident by an increase in phosphorylation of PERK, PKR, and eIF2alpha as well as the expression of GRP78. PMID:18508033 An eIF2alpha siRNA significantly reduced rotenone cytotoxicity. |
| GO:0034976 response to endoplasmic reticulum stress | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: ISS from mouse (response to ER stress). Reason: As for the other response-to-ER-stress rows. Supporting Evidence: file:human/EIF2S1/EIF2S1-uniprot.txt Phosphorylation at Ser-52 by the EIF2AK3/PERK protein kinase occurs in response to the unfolded protein response (PubMed:10026192). |
| GO:0036490 regulation of translation in response to endoplasmic reticulum stress | IMP PMID:18508033 GSK3beta and endoplasmic reticulum stress mediate rotenone-i... | ACCEPT | Summary: IMP (eIF2alpha siRNA) for regulation of translation in response to ER stress. Reason: Regulation of translation in response to ER stress is exactly what phosphorylated eIF2alpha does (PERK phosphorylation inhibits eIF2B and attenuates initiation). The cached abstract shows the knockdown and ER-stress readouts; the curator read the full text. Supporting Evidence: PMID:18508033 An eIF2alpha siRNA significantly reduced rotenone cytotoxicity. PMID:22934019 PERK homodimerizes and phosphorylates eIF2Ξ± to inhibit general protein translation. |
| GO:0036499 PERK-mediated unfolded protein response | IDA PMID:31023583 ER and Nutrient Stress Promote Assembly of Respiratory Chain... | ACCEPT | Summary: Balsa et al. 2019 showed the PERK-eIF2alpha-ATF4 axis drives SCAF1/COX7A2L induction and respiratory supercomplex assembly under ER and nutrient stress. Reason: eIF2alpha is the PERK substrate whose phosphorylation transduces the PERK branch of the UPR (via eIF2B inhibition and uORF-driven ATF4 translation); it does work in the pathway, not merely serving as a substrate. Supporting Evidence: PMID:31023583 The PERK-eIF2Ξ±-ATF4 axis increases supercomplex assembly factor 1 (SCAF1 or COX7A2L), promoting SCs and enhanced mitochondrial respiration. |
| GO:0036499 PERK-mediated unfolded protein response | IDA PMID:33384352 QRICH1 dictates the outcome of ER stress through transcripti... | ACCEPT | Summary: QRICH1 identified as an effector of the PERK-eIF2alpha axis. Reason: Supports eIF2alpha as the signal transducer of the PERK arm. Supporting Evidence: PMID:33384352 We identified QRICH1 as a key effector of the PERK-eIF2Ξ± axis of the UPR. |
| GO:0036499 PERK-mediated unfolded protein response | NAS PMID:22934019 The endoplasmic reticulum stress response in aging and age-r... | ACCEPT | Summary: Review of ER stress in aging (NAS). Reason: The review states the canonical PERK-eIF2alpha step of the UPR. Supporting Evidence: PMID:22934019 PERK homodimerizes and phosphorylates eIF2Ξ± to inhibit general protein translation. |
| GO:0043022 ribosome binding | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: IBA ribosome binding (PTN000063907). Reason: As part of the ternary complex and 43S/48S pre-initiation complex, eIF2 binds the 40S subunit; true but a component of the initiation-factor activity rather than a separate function. Supporting Evidence: PMID:23063529 Together with GTP and initiator methionyl-tRNA, translation initiation factor eIF2 forms a ternary complex that binds the 40S ribosome and then scans an mRNA to select the AUG start codon for protein synthesis. |
| GO:0043022 ribosome binding | IDA PMID:17894550 The N-terminal region of ABC50 interacts with eukaryotic ini... | KEEP AS NON CORE | Summary: eIF2 association with 80S ribosomal and polysomal fractions, modulated by ABC50 (abstract-only). Reason: Supports ribosome association of eIF2; peripheral to the core activity. Supporting Evidence: PMID:17894550 Expression of a mutant of ABC50 in which both sites are mutated to alanine markedly decreased the association of eIF2 with 80S ribosomal and polysomal fractions. |
| GO:0044207 translation initiation ternary complex | IEA GO_REF:0000107 | ACCEPT | Summary: Ensembl ortholog transfer from rat for translation initiation ternary complex. Reason: eIF2 forms the eIF2-GTP-Met-tRNAi ternary complex; EIF2S1 is a subunit. Supporting Evidence: file:human/EIF2S1/EIF2S1-uniprot.txt Member of the eIF2 complex that functions in the early steps of protein synthesis by forming a ternary complex with GTP and initiator tRNA |
| GO:0045202 synapse | IEA GO_REF:0000107 | MARK AS OVER ANNOTATED | Summary: Ensembl ortholog transfer of synapse (is_active_in) from mouse. Reason: eIF2alpha is a ubiquitous cytosolic factor; presence of translation machinery in neurons including synaptic compartments does not make synapse an informative location of its function, and no human evidence supports it. Supporting Evidence: file:human/EIF2S1/EIF2S1-uniprot.txt Cytoplasm, cytosol |
| GO:0070062 extracellular exosome | HDA PMID:20458337 MHC class II-associated proteins in B-cell exosomes and pote... | MARK AS OVER ANNOTATED | Summary: B-cell exosome proteomics identified EIF2S1. Reason: Abundant cytosolic proteins are routinely captured in exosome proteomes; no function there. Supporting Evidence: PMID:20458337 we first analyzed the total proteome of highly purified B cell-derived exosomes using sensitive and accurate mass spectrometry (MS), and identified 539 proteins |
| GO:0097451 glial limiting end-foot | IEA GO_REF:0000107 | MARK AS OVER ANNOTATED | Summary: Ensembl ortholog transfer from rat of glial limiting end-foot. Reason: A tissue-specific immunolocalization of a ubiquitous initiation factor, not informative of its function; no human evidence. Supporting Evidence: file:human/EIF2S1/EIF2S1-uniprot.txt Cytoplasm, cytosol |
| GO:0140468 HRI-mediated signaling | IDA PMID:32132706 A pathway coordinated by DELE1 relays mitochondrial stress t... | ACCEPT | Summary: DELE1-HRI relay of mitochondrial stress (Fessler et al. 2020); eIF2alpha phosphorylation is the output of HRI. Reason: eIF2alpha is the downstream protein to which HRI relays the signal; phosphorylated eIF2 then inhibits eIF2B and induces ATF4/CHOP. It is a working component of HRI-mediated signaling (abstract-only cache; deferring to the curator). Supporting Evidence: PMID:32132706 eIF2Ξ± phosphorylation is mediated by the four eIF2Ξ± kinases GCN2, HRI, PERK and PKR, which are activated by diverse types of cellular stress |
| GO:0140468 HRI-mediated signaling | IDA PMID:32132707 Mitochondrial stress is relayed to the cytosol by an OMA1-DE... | ACCEPT | Summary: OMA1-DELE1-HRI pathway (Guo et al. 2020); DELE1 stimulates HRI eIF2alpha kinase activity in vitro with purified eIF2alpha. Reason: Direct evidence that eIF2alpha is the HRI substrate in this signaling pathway. Supporting Evidence: PMID:32132707 Using purified HRI, eIF2Ξ± and DELE1, we showed that DELE1 stimulates eIF2Ξ± kinase activity of HRI in vitro |
| GO:0140468 HRI-mediated signaling | IDA PMID:38340717 The HRI branch of the integrated stress response selectively... | ACCEPT | Summary: HRI branch of the ISR triggers mitophagy through mitochondrial p-eIF2alpha. Reason: Phosphorylated eIF2alpha is the effector of HRI signaling in this study. Supporting Evidence: PMID:38340717 Activation of the HRI branch results in mitochondrial localization of phosphorylated eukaryotic initiation factor 2, which we show is sufficient to induce mitophagy. |
| GO:0160296 cap-dependent translation initiation factor activity | IDA PMID:16289705 An efficient mammalian cell-free translation system suppleme... | MODIFY | Summary: UniProt-assigned IDA to cap-dependent translation initiation factor activity from the HeLa cell-free translation paper. The same term types an EIF2S1 node in GO-CAM gomodel:66b5638000001589 and its clones. Reason: GO:0160296 is defined by recognition and binding of the 7-methylguanosine cap, which is eIF4E/eIF4F activity, not eIF2's. The cited abstract shows eIF2 stimulated capped, uncapped and EMCV-IRES mRNAs alike, while eIF4E alone was cap-specific. The essence (initiation factor) is sound; the correct term is the parent GO:0003743. Proposed replacements: translation initiation factor 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. PMID:16289705 eIF4E specifically stimulated capped mRNA translation |
| GO:0160297 IRES-mediated translation initiation factor activity | IDA PMID:16289705 An efficient mammalian cell-free translation system suppleme... | MODIFY | Summary: UniProt-assigned IDA to IRES-mediated translation initiation factor activity from the same cell-free translation paper. The same term types the duplicate EIF2S1 node (has_input ATF4) in GO-CAM gomodel:66b5638000001589. Reason: GO:0160297 is defined by interaction with IRESs. eIF2 does not bind IRESs; it supports IRES-driven translation as a general factor, exactly as it supports capped translation. ATF4 induction during the ISR is uORF-mediated delayed reinitiation, not IRES use. The correct term is the parent GO:0003743. Proposed replacements: translation initiation factor 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:1904373 response to kainic acid | IEA GO_REF:0000107 | MARK AS OVER ANNOTATED | Summary: Ensembl ortholog transfer from rat of response to kainic acid. Reason: A pharmacological-response phenotype in rat brain; eIF2alpha phosphorylation is a generic stress output, and this term adds nothing about function. Supporting Evidence: file:human/EIF2S1/EIF2S1-uniprot.txt EIF2S1/eIF2-alpha is a key component of the integrated stress response (ISR), required for adaptation to various stress |
| GO:1990737 response to manganese-induced endoplasmic reticulum stress | IEA GO_REF:0000107 | MARK AS OVER ANNOTATED | Summary: Ensembl ortholog transfer from rat of response to manganese-induced ER stress. Reason: Toxicant-specific instance of the general ER stress response, already covered by the PERK-mediated UPR rows. Supporting Evidence: file:human/EIF2S1/EIF2S1-uniprot.txt Phosphorylation at Ser-52 by the EIF2AK3/PERK protein kinase occurs in response to the unfolded protein response (PubMed:10026192). |
| GO:2000676 positive regulation of type B pancreatic cell apoptotic process | IEA GO_REF:0000107 | MARK AS OVER ANNOTATED | Summary: Ensembl ortholog transfer from rat of positive regulation of beta-cell apoptosis. Reason: A cell-type-specific downstream outcome of sustained eIF2alpha phosphorylation (CHOP induction), not a function of eIF2alpha; no human evidence. Supporting Evidence: file:human/EIF2S1/EIF2S1-uniprot.txt EIF2S1/eIF2-alpha is a key component of the integrated stress response (ISR), required for adaptation to various stress |
| GO:1990624 guanyl nucleotide exchange factor inhibitor activity | IC PMID:10613902 RNA-binding proteins TIA-1 and TIAR link the phosphorylation... | NEW | Summary: Proposed: Ser51-phosphorylated eIF2 binds eIF2B tightly and blocks its GDP-GTP exchange activity. Reason: GO:1990624 is defined as binding to and inhibiting a guanyl nucleotide exchange factor, which is exactly what phosphorylated eIF2 does to eIF2B: phosphorylation raises eIF2's affinity for eIF2B and prevents nucleotide exchange, and this inhibition of the exchange factor is the mechanism by which the integrated stress response attenuates initiation. eIF2alpha itself is the entity that performs the inhibition (its phosphorylated form is the inhibitor), so this is participation, not substrate status. No existing row captures this regulatory activity; GO:0003743 covers only the productive initiation-factor role. Supporting Evidence: file:human/EIF2S1/EIF2S1-uniprot.txt Activity is regulated by phosphorylation at Ser-49 and Ser-52, which stabilizes the eIF2/GDP/eIF2B complex and prevents the eIF2B-mediated exchange of GDP for GTP PMID:10613902 Phosphorylation of eIF-2Ξ± increases the affinity of eIF-2 for eIF-2B, and prevents the exchange of GDP for GTP, thereby inhibiting the formation of preinitiation complexes. |
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Download this section (compressed HTML)Q: The inhibitory state of phosphorylated eIF2 (tight, non-productive binding to eIF2B that blocks its exchange activity) fits GO:1990624 guanyl nucleotide exchange factor inhibitor activity, which this review uses for the phospho-eIF2 core function. Should ISR GO-CAMs type the phospho-eIF2 node with GO:1990624 (negatively regulating eIF2B GO:0005085) instead of duplicating EIF2S1 with cap-dependent and IRES-mediated activity terms, and should EIF2S1 carry a GO:1990624 annotation from PMID:10613902-type evidence?
Q: The UniProt-assigned GO:0160296 and GO:0160297 rows on EIF2S1 (PMID:16289705) mirror the EIF2S1 activity typing in GO-CAM gomodel:66b5638000001589 and its clones; should both be replaced by GO:0003743 at source?
Experiment: Tether wild-type, S51D and S51A eIF2alpha to the mitochondrial surface in cells lacking EIF2S2 or EIF2S3 incorporation (or with eIF2B overexpression), and use proximity labelling to identify autophagy factors recruited by mitochondrial phospho-eIF2.
Hypothesis: Phosphorylated eIF2 on the mitochondrial surface recruits autophagy machinery directly, independently of its translational effects.
What is not known β curated, literature-grounded statements of the open unknowns (the inverse of core functions).
Gap: How phosphorylated eIF2 on the mitochondrial surface triggers mitophagy, and why HRI-generated but not PERK-generated phospho-eIF2 accumulates there, is unknown.
OPEN BIOLOGY RESIDUAL_SUBGAP
What is known: Tethering phosphomimetic eIF2alpha to mitochondria is sufficient for mitophagy without phospho-ubiquitin accumulation, and ISRIB does not block DFP-induced mitophagy, but no receptor or adaptor linking p-eIF2 to autophagosome formation has been identified.
Provenance (the field's own admissions):
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