EIF4E2

Summary: 4EHP binds the m7G mRNA cap - its defining, structurally confirmed molecular function and the basis of its repressor activity. Core.

Reason: Cap binding is established by structural and biochemical studies and underlies the competitive repression of cap-dependent initiation.

Summary: EIF4E2 supports oxygen-regulated translation initiation in an eIF4E2/eIF4A/eIF4G3 complex.

Reason: PTHR11960 places initiation-factor, initiation-process and eIF4F-complex assertions at PTN000238660. The prior review generalized inability to recruit canonical eIF4G1 into inability to recruit any eIF4G. Primary studies PMID:22678294 and PMID:26854219 demonstrate hypoxic translation and assembly of eIF4E2 with eIF4A and eIF4G3 (eIF4FH), together with functional depletion and polysome evidence. The GO eIF4F definition is not restricted to the EIF4E1/EIF4G1 paralog combination. These activities coexist with GIGYF-dependent repression, so the repressor function does not justify rejecting the inherited initiation role.

Summary: EIF4E2 supports oxygen-regulated translation initiation in an eIF4E2/eIF4A/eIF4G3 complex.

Reason: PTHR11960 places initiation-factor, initiation-process and eIF4F-complex assertions at PTN000238660. The prior review generalized inability to recruit canonical eIF4G1 into inability to recruit any eIF4G. Primary studies PMID:22678294 and PMID:26854219 demonstrate hypoxic translation and assembly of eIF4E2 with eIF4A and eIF4G3 (eIF4FH), together with functional depletion and polysome evidence. The GO eIF4F definition is not restricted to the EIF4E1/EIF4G1 paralog combination. These activities coexist with GIGYF-dependent repression, so the repressor function does not justify rejecting the inherited initiation role.

Summary: EIF4E2 supports oxygen-regulated translation initiation in an eIF4E2/eIF4A/eIF4G3 complex.

Reason: PTHR11960 places initiation-factor, initiation-process and eIF4F-complex assertions at PTN000238660. The prior review generalized inability to recruit canonical eIF4G1 into inability to recruit any eIF4G. Primary studies PMID:22678294 and PMID:26854219 demonstrate hypoxic translation and assembly of eIF4E2 with eIF4A and eIF4G3 (eIF4FH), together with functional depletion and polysome evidence. The GO eIF4F definition is not restricted to the EIF4E1/EIF4G1 paralog combination. These activities coexist with GIGYF-dependent repression, so the repressor function does not justify rejecting the inherited initiation role. The focused OpenScientist report supports the dual initiation/repression functions but incorrectly states that no primary complex-composition evidence exists: PMID:26854219 Fig2C/S2D directly reports endogenous human eIF4E2/eIF4A/eIF4G3 pull-downs, and PMID:22678294 reports eIF4A recruitment. Absence of an experimental GO row or Complex Portal entry is not negative experimental evidence. The cited GIGYF/4E-BP structural study does not test hypoxic eIF4G3 assembly; complex membership also does not require a demonstrated purified binary EIF4E2-EIF4G3 interaction. Retain the supported inherited complex annotation.

Summary: P-body localization. Consistent with 4EHP's role in miRNA-mediated repression and mRNA storage/decay; corroborated by IDA.

Reason: 4EHP localizes to P-bodies and acts there in miRNA silencing.

Summary: Generic RNA binding (IEA). 4EHP binds the m7G cap of mRNAs; the more specific cap- binding MF is the informative term.

Reason: EIF4E2 directly recognizes the mRNA cap and regulates translation through both activating and repressive complexes. This broad molecular function is compatible with the more specific cap-binding annotation and describes a core biochemical property.

Summary: EIF4E2 supports oxygen-regulated translation initiation in an eIF4E2/eIF4A/eIF4G3 complex.

Reason: PTHR11960 places initiation-factor, initiation-process and eIF4F-complex assertions at PTN000238660. The prior review generalized inability to recruit canonical eIF4G1 into inability to recruit any eIF4G. Primary studies PMID:22678294 and PMID:26854219 demonstrate hypoxic translation and assembly of eIF4E2 with eIF4A and eIF4G3 (eIF4FH), together with functional depletion and polysome evidence. The GO eIF4F definition is not restricted to the EIF4E1/EIF4G1 paralog combination. These activities coexist with GIGYF-dependent repression, so the repressor function does not justify rejecting the inherited initiation role.

Summary: Cytoplasmic localization (IEA). Consistent with 4EHP's cytosolic translation- repression activity.

Reason: 4EHP is a cytoplasmic cap-binding protein; supported by direct evidence.

Summary: EIF4E2 supports oxygen-regulated translation initiation in an eIF4E2/eIF4A/eIF4G3 complex.

Reason: PTHR11960 places initiation-factor, initiation-process and eIF4F-complex assertions at PTN000238660. The prior review generalized inability to recruit canonical eIF4G1 into inability to recruit any eIF4G. Primary studies PMID:22678294 and PMID:26854219 demonstrate hypoxic translation and assembly of eIF4E2 with eIF4A and eIF4G3 (eIF4FH), together with functional depletion and polysome evidence. The GO eIF4F definition is not restricted to the EIF4E1/EIF4G1 paralog combination. These activities coexist with GIGYF-dependent repression, so the repressor function does not justify rejecting the inherited initiation role.

Summary: Generic IPI protein-binding annotation. Uninformative as a molecular function.

Reason: Remove the uninformative generic protein binding label while retaining the documented interaction evidence. Cap binding, translation initiation, repression and the informative ligase-binding annotation describe the supported functional roles; no new activity is inferred from interaction alone.

Summary: Generic IPI protein-binding annotation from an mRNA-degradation interaction framework. Uninformative as a molecular function.

Reason: Remove the uninformative generic protein binding label while retaining the documented interaction evidence. Cap binding, translation initiation, repression and the informative ligase-binding annotation describe the supported functional roles; no new activity is inferred from interaction alone.

Summary: Generic IPI protein-binding annotation. Uninformative as a molecular function.

Reason: Remove the uninformative generic protein binding label while retaining the documented interaction evidence. Cap binding, translation initiation, repression and the informative ligase-binding annotation describe the supported functional roles; no new activity is inferred from interaction alone.

Summary: Generic IPI protein-binding annotation. Uninformative as a molecular function.

Reason: Remove the uninformative generic protein binding label while retaining the documented interaction evidence. Cap binding, translation initiation, repression and the informative ligase-binding annotation describe the supported functional roles; no new activity is inferred from interaction alone.

Summary: Generic IPI protein-binding annotation. Uninformative as a molecular function.

Reason: Remove the uninformative generic protein binding label while retaining the documented interaction evidence. Cap binding, translation initiation, repression and the informative ligase-binding annotation describe the supported functional roles; no new activity is inferred from interaction alone.

Summary: Generic protein-binding annotation from the HI-III human interactome (Y2H). Uninformative as a molecular function.

Reason: Remove the uninformative generic protein binding label while retaining the documented interaction evidence. Cap binding, translation initiation, repression and the informative ligase-binding annotation describe the supported functional roles; no new activity is inferred from interaction alone.

Summary: Generic IPI protein-binding annotation. Uninformative as a molecular function.

Reason: Remove the uninformative generic protein binding label while retaining the documented interaction evidence. Cap binding, translation initiation, repression and the informative ligase-binding annotation describe the supported functional roles; no new activity is inferred from interaction alone.

Summary: Generic IPI protein-binding annotation. Uninformative as a molecular function.

Reason: Remove the uninformative generic protein binding label while retaining the documented interaction evidence. Cap binding, translation initiation, repression and the informative ligase-binding annotation describe the supported functional roles; no new activity is inferred from interaction alone.

Summary: Generic IPI protein-binding annotation. Uninformative as a molecular function.

Reason: Remove the uninformative generic protein binding label while retaining the documented interaction evidence. Cap binding, translation initiation, repression and the informative ligase-binding annotation describe the supported functional roles; no new activity is inferred from interaction alone.

Summary: Generic protein-binding annotation from a neurodegenerative-disease interactome mapping study. Uninformative as a molecular function.

Reason: Remove the uninformative generic protein binding label while retaining the documented interaction evidence. Cap binding, translation initiation, repression and the informative ligase-binding annotation describe the supported functional roles; no new activity is inferred from interaction alone.

Summary: Generic protein-binding annotation from the BioPlex interactome. Uninformative as a molecular function.

Reason: Remove the uninformative generic protein binding label while retaining the documented interaction evidence. Cap binding, translation initiation, repression and the informative ligase-binding annotation describe the supported functional roles; no new activity is inferred from interaction alone.

Summary: Generic protein-binding annotation from a proximity-biotinylation map. Uninformative as a molecular function.

Reason: Remove the uninformative generic protein binding label while retaining the documented interaction evidence. Cap binding, translation initiation, repression and the informative ligase-binding annotation describe the supported functional roles; no new activity is inferred from interaction alone.

Summary: Generic IPI protein-binding annotation. Uninformative as a molecular function.

Reason: Remove the uninformative generic protein binding label while retaining the documented interaction evidence. Cap binding, translation initiation, repression and the informative ligase-binding annotation describe the supported functional roles; no new activity is inferred from interaction alone.

Summary: Direct cytosol localization. Consistent with 4EHP's cytosolic function.

Reason: Cytosolic localization is experimentally supported.

Summary: ComplexPortal-derived annotation reflecting the 4EHP-GIGYF co-translational mRNA- decay complex. The biology is correct but 'pre-mRNA catabolic process' is imprecise; substrates are mature mRNAs.

Reason: The complex triggers co-translational decay of mature mRNAs, not pre-mRNA turnover.

Proposed replacements: nuclear-transcribed mRNA catabolic process

Summary: Direct evidence for mRNA cap binding (m7GTP-bound crystal structure). Core MF.

Reason: Structural and biochemical data directly demonstrate cap binding by 4EHP.

Summary: Direct evidence for m7G cap binding in the context of IFNB1 repression. Core MF.

Reason: 4EHP cap binding is required for its repression of target mRNAs including IFNB1.

Summary: Core function: 4EHP (with GIGYF2) inhibits translation initiation on defective/ ribosome-stalling mRNAs as part of RQC.

Reason: Direct evidence places 4EHP/GIGYF2 as inhibitors of initiation on faulty messages.

Summary: 4EHP/GIGYF2 repress IFNB1 translation initiation; co-opted by SARS-CoV-2 nsp2. Supports the core repressor function.

Reason: Direct evidence of 4EHP-mediated repression of IFNB1 translation.

Summary: 4EHP/GIGYF2 repress IFNB1 (type I IFN) translation. A genuine, context-specific role rather than the core, ubiquitous function.

Reason: The IFN-repression role is a specific outcome of 4EHP's general repression activity on IFNB1 mRNA, exploited during SARS-CoV-2 infection.

Summary: EIF4E2 suppresses additional translation initiation on faulty messages, acting alongside ribosome quality-control machinery.

Reason: GO:0072344 specifically requires freeing an already stalled cytosolic ribosome. The full primary study instead establishes cap-dependent inhibition of new initiation by 4EHP/GIGYF2, including genetic separation from degradation machinery. Participation in the larger quality-control response does not demonstrate release of the stalled ribosome. Replace with the experimentally measured negative regulation of translational initiation, already independently annotated here.

Proposed replacements: negative regulation of translational initiation

Summary: 4EHP is an integral component of miRNA-mediated silencing; its cap-binding activity contributes to translational silencing of miRNA targets via 4E-T and CCR4-NOT.

Reason: Direct evidence that 4EHP cap binding contributes to miRNA-mediated translational silencing.

Summary: IPI annotation for the direct 4EHP-GIGYF interaction (via the GIGYF 4EHP-binding motif). Functionally central but 'protein binding' is too generic; the GIGYF-binding interaction underlies repression.

Reason: Remove the uninformative generic protein binding label while retaining the documented interaction evidence. Cap binding, translation initiation, repression and the informative ligase-binding annotation describe the supported functional roles; no new activity is inferred from interaction alone.

Summary: Direct P-body localization, consistent with 4EHP's role in repressed-mRNP/miRNA silencing.

Reason: 4EHP localizes to P-bodies, consistent with its repression function.

Summary: IPI annotation for the 4EHP-4E-T (EIF4ENIF1) interaction, which influences 4EHP's cellular distribution. Real but the generic term is uninformative.

Reason: Remove the uninformative generic protein binding label while retaining the documented interaction evidence. Cap binding, translation initiation, repression and the informative ligase-binding annotation describe the supported functional roles; no new activity is inferred from interaction alone.

Summary: IPI annotation from the miRNA-silencing study (interactions with 4E-T/CCR4-NOT machinery). The functional role is captured by the miRNA-silencing BP.

Reason: Remove the uninformative generic protein binding label while retaining the documented interaction evidence. Cap binding, translation initiation, repression and the informative ligase-binding annotation describe the supported functional roles; no new activity is inferred from interaction alone.

Summary: Direct cytoplasmic localization.

Reason: 4EHP is a cytoplasmic protein, supported by direct evidence.

Summary: RNA binding from a proteome-wide mRNA-interactome capture study. Subsumed by the specific cap-binding MF.

Reason: EIF4E2 directly recognizes the mRNA cap and regulates translation through both activating and repressive complexes. This broad molecular function is compatible with the more specific cap-binding annotation and describes a core biochemical property.

Summary: Cytosol localization (Reactome TAS). Consistent with 4EHP's cytosolic function.

Reason: Cytosolic localization is well supported.

Summary: Duplicate cytosol localization (Reactome TAS).

Reason: Cytosolic localization is well supported.

Summary: Genetic/biochemical evidence that the 4EHP-GIGYF2 complex represses translation; disruption increases translation and causes perinatal lethality in mice. Core.

Reason: Disruption of the m4EHP-GIGYF2 complex increases translation, directly demonstrating 4EHP's negative regulation of translation.

Summary: 4EHP binds the RBR E3 ligase ARIH1/HHARI, which promotes its ubiquitylation. A real, specific interaction (4EHP is the substrate/partner, not the ligase).

Reason: Direct evidence that HHARI/ARIH1 (a ubiquitin protein ligase) interacts with and ubiquitylates 4EHP.

Summary: Generic protein-binding annotation from the structural/cap-binding study. The informative MF (cap binding) is captured separately.

Reason: Remove the uninformative generic protein binding label while retaining the documented interaction evidence. Cap binding, translation initiation, repression and the informative ligase-binding annotation describe the supported functional roles; no new activity is inferred from interaction alone.

Summary: Cap binding (TAS, original characterization). 4EHP is an eIF4E-related cap-binding protein. Core MF.

Reason: The original cloning/characterization established 4EHP as a cap-binding protein.

Summary: EIF4E2 binds the mRNA cap and functions in translation-regulatory complexes, including productive hypoxic initiation and GIGYF-dependent repression.

Reason: EIF4E2 directly recognizes the mRNA cap and regulates translation through both activating and repressive complexes. This broad molecular function is compatible with the more specific cap-binding annotation and describes a core biochemical property.