eif-2alpha (Y37E3.10) encodes the alpha subunit of eukaryotic translation initiation factor 2 (eIF2) in Caenorhabditis elegans. It has an N-terminal S1 RNA-binding (OB-fold) domain, a helical middle domain and a C-terminal domain, ending in an acidic disordered tail. As part of the eIF2 heterotrimer, which delivers initiator Met-tRNAi to the 40S subunit as a GTP-bound ternary complex, it acts in the 43S/48S preinitiation complex during cap-dependent translation initiation. eIF2alpha is the regulatory subunit of eIF2. Phosphorylation of Ser49 (mammalian Ser51) by the eIF2alpha kinases PEK-1 (PERK) and GCN-2 blocks eIF2B-catalysed GDP/GTP exchange. This attenuates global translation in the integrated stress response, including the ER unfolded protein response, mitochondrial stress, nutrient limitation, osmotic, heat and oxidative stress. Non-phosphorylatable S49A mutants are viable, develop faster, and are needed for translational repression and wild-type survival under ER stress. Phosphorylation in ASI sensory neurons modulates dauer entry, and semaphorin signaling lowers eIF2alpha phosphorylation during epidermal morphogenesis.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0003676 nucleic acid binding | IEA GO_REF:0000002 | ACCEPT | Summary: InterPro S1-domain mapping to nucleic acid binding. Reason: eIF2alpha carries an N-terminal S1/OB-fold domain, which in eIF2alpha contacts mRNA and the initiator tRNA in the preinitiation complex. The broad IEA term is correct, though less informative than the RNA binding row. Supporting Evidence: GO_REF:0000002 Gene Ontology annotation through association of InterPro records with GO terms |
| GO:0003723 RNA binding | IEA GO_REF:0000002 | ACCEPT | Summary: InterPro eIF2alpha/S1 domain mapping to RNA binding. Reason: The eIF2alpha S1 domain is an RNA-binding OB fold, and eIF2alpha is part of the eIF2 ternary complex that carries Met-tRNAi to the ribosome. The mapping is appropriate. RNA binding is a supporting feature of the translation initiation factor activity, not a separate function. Supporting Evidence: PMID:32292896 The eIF2 trimer is required for delivering charged tRNAMet to the ribosome in a reaction requiring the hydrolysis of GTP to GDP |
| GO:0003743 translation initiation factor activity | IBA GO_REF:0000033 | ACCEPT | Summary: Phylogenetic inference of translation initiation factor activity from the eIF2alpha family node (yeast SUI2, human EIF2S1, mouse, fly). Reason: eif-2alpha is the single-copy C. elegans ortholog of eIF2alpha and lies inside the PTHR10602 clade, where this activity is experimentally grounded in yeast and mammals. The worm protein is described as the eIF2 alpha subunit, and its Ser49 phosphorylation controls translation as in other eukaryotes (PMID:32292896, PMID:38161330). This is the core molecular function. Supporting Evidence: PMID:32292896 The gene eif-2alpha (Y37E3.10) in C. elegans encodes for the alpha subunit of eukaryotic translation initiation factor 2 (eIF2). |
| GO:0003743 translation initiation factor activity | IEA GO_REF:0000002 | ACCEPT | Summary: InterPro TIF_2_asu mapping to translation initiation factor activity. Reason: The InterPro family IPR011488 (translation initiation factor 2, alpha subunit) is diagnostic, and the mapping agrees with the IBA row. Supporting Evidence: PMID:32292896 The gene eif-2alpha (Y37E3.10) in C. elegans encodes for the alpha subunit of eukaryotic translation initiation factor 2 (eIF2). |
| GO:0005850 eukaryotic translation initiation factor 2 complex | IBA GO_REF:0000033 | ACCEPT | Summary: eIF2alpha is the alpha subunit of the eIF2 heterotrimer. Reason: The alpha subunit is by definition part of the eIF2 complex, and the IBA is well placed in a single-copy orthologous family. Supporting Evidence: PMID:32292896 The gene eif-2alpha (Y37E3.10) in C. elegans encodes for the alpha subunit of eukaryotic translation initiation factor 2 (eIF2). |
| GO:0006413 translational initiation | IBA GO_REF:0000033 | ACCEPT | Summary: eIF2 acts in translational initiation. Reason: Core process of eIF2. In C. elegans, blocking Ser49 phosphorylation abolishes stress-induced translational repression, which shows that this subunit controls initiation in vivo (PMID:38161330). Supporting Evidence: PMID:38161330 In each case, phosphorylation of eIF2Ξ± results in rapid attenuation of mRNA translation and redeployment of remaining translation to stress responsive genes |
| GO:0033290 eukaryotic 48S preinitiation complex | IBA GO_REF:0000033 | ACCEPT | Summary: The eIF2 ternary complex is a component of the 43S/48S preinitiation complex. Reason: The eIF2-GTP-Met-tRNAi ternary complex is a defining constituent of the 48S preinitiation complex in all eukaryotes, so the IBA is sound. Supporting Evidence: PMID:32292896 The eIF2 trimer is required for delivering charged tRNAMet to the ribosome in a reaction requiring the hydrolysis of GTP to GDP |
| GO:0043022 ribosome binding | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: eIF2alpha contacts the 40S subunit within the preinitiation complex. Reason: In 48S structures the eIF2alpha subunit contacts the small ribosomal subunit near the E site, which is the basis of the human annotation propagated here. This is consistent with the subunit's position, but it is a structural feature of initiation factor activity rather than a separate function, so it is kept as non-core. Supporting Evidence: PMID:32292896 The eIF2 trimer is required for delivering charged tRNAMet to the ribosome in a reaction requiring the hydrolysis of GTP to GDP |
| GO:0036499 PERK-mediated unfolded protein response | IMP PMID:38161330 The integrated stress response protects against ER stress bu... | NEW | Summary: The phospho-acceptor Ser49 of EIF-2alpha is required for ER-stress-induced translational repression and survival. Reason: Phosphorylated eIF2alpha is the effector of the PERK branch. It binds and inhibits eIF2B, so the product itself carries out translational attenuation and is not only a substrate. In C. elegans, the non-phosphorylatable eif-2alpha(rog3) S49A mutant lacks PEK-1-dependent translational repression under tunicamycin and does not survive ER stress like wild type (PMID:38161330). Comparator check: human EIF2S1 (P05198) carries GO:0036499 involved_in by IDA in GOA, assigned by UniProt from PMID:31023583 and PMID:33384352 (plus a ParkinsonsUK-UCL NAS from PMID:22934019; QuickGO query 2026-10-09), so the term is used for the alpha subunit. The ER UPR module (modules/er_unfolded_protein_response.yaml) is consistent with this: its PERK arm models eIF2alpha as a participant annoton, with translation initiation factor activity (GO:0003743) and GO:0036499 as its process, alongside its role as the PEK-1 kinase target. Supporting Evidence: PMID:38161330 The ISR was not dispensable under ER stress conditions, as demonstrated by the requirement for PERK and eIF2Ξ± phosphorylation for decreased translation and wild type-like survival. PMID:38161330 We also included a mutant eif-2Ξ±(rog3), hitherto referred to simply as eif-2Ξ±, with serine 49 replaced by alanine, which cannot be phosphorylated. |
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Download this section (compressed HTML)Q: GO has no molecular-function term for the inhibitory activity of phosphorylated eIF2 toward eIF2B ("guanyl-nucleotide exchange factor inhibitor activity" is the closest). Should a phospho-eIF2alpha-specific activity be modeled in GO-CAMs of the PERK and GCN2 branches, or should eIF2alpha stay a kinase target only?
Experiment: Phosphoproteomics of gcn-2;pek-1 versus eif-2alpha(S49A) worms under fasting, and testing of additional eIF2alpha phosphosites by mutation.
Hypothesis: The residual eIF2-independent effects of GCN-2 and PEK-1 on dietary restriction lifespan act through other substrates or other eIF2alpha sites.
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