id: O60573
gene_symbol: EIF4E2
product_type: PROTEIN
status: COMPLETE
taxon:
  id: NCBITaxon:9606
  label: Homo sapiens
description: >-
  EIF4E2 (eIF4E homologous protein, 4EHP) is a class II member of the eIF4E cap-binding
  protein family. It recognizes and binds the 7-methylguanosine (m7G) mRNA 5' cap but,
  unlike the canonical eIF4E, cannot bind the scaffold eIF4G; it therefore competes with
  eIF4E for the cap and blocks assembly of the eIF4F initiation complex, acting as a
  repressor of cap-dependent translation initiation rather than a promoter of it. 4EHP is
  the catalytic-cap-binding core of the 4EHP-GIGYF2 translational-repressor module: bound
  to GIGYF2 (and ZNF598/DDX6) it sequesters the cap of specific mRNAs to suppress their
  translation, including as part of ribosome-associated quality control, where it lowers
  the translational load on messages that cause ribosome stalling. 4EHP is also an integral
  component of miRNA-mediated silencing, contributing cap-binding activity that, via 4E-T
  and the CCR4-NOT complex, represses translation of miRNA targets, and it mediates miR-34a-
  directed negative-feedback control of IFNB1 (type I interferon) production - a circuit
  co-opted by SARS-CoV-2 nsp2. It localizes to the cytoplasm and to P-bodies and is itself
  a substrate for ubiquitylation by the RBR E3 ligase ARIH1/HHARI.
existing_annotations:
- term:
    id: GO:0000340
    label: RNA 7-methylguanosine cap binding
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: enables
  review:
    summary: >-
      4EHP binds the m7G mRNA cap - its defining, structurally confirmed molecular
      function and the basis of its repressor activity. Core.
    action: ACCEPT
    reason: >-
      Cap binding is established by structural and biochemical studies and underlies the
      competitive repression of cap-dependent initiation.
    supported_by:
    - reference_id: PMID:17368478
      supporting_text: Structures of the human eIF4E homologous protein, h4EHP, in its m7GTP-bound and unliganded forms.
- term:
    id: GO:0003743
    label: translation initiation factor activity
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: enables
  review:
    summary: >-
      Phylogenetic transfer from the eIF4E family. 4EHP is NOT a canonical initiation
      factor - it cannot bind eIF4G and represses rather than promotes initiation. This
      MF is misleading for 4EHP.
    action: MODIFY
    reason: >-
      Unlike eIF4E, 4EHP cannot recruit eIF4G and does not promote initiation; it competes
      for the cap to block eIF4F assembly. A translation-repressor MF is appropriate, not
      'translation initiation factor activity'.
    proposed_replacement_terms:
    - id: GO:0045182
      label: translation regulator activity
    supported_by:
    - reference_id: file:human/EIF4E2/EIF4E2-uniprot.txt
      supporting_text: it is unable to bind eIF4G (EIF4G1, EIF4G2 or EIF4G3),
- term:
    id: GO:0006413
    label: translational initiation
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: involved_in
  review:
    summary: >-
      Phylogenetic transfer. 4EHP participates in initiation only as a repressor; the
      generic 'translational initiation' over-states a positive role.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      4EHP represses, rather than mediates, cap-dependent initiation; the specific role is
      better captured by negative regulation of translational initiation.
    supported_by:
    - reference_id: file:human/EIF4E2/EIF4E2-uniprot.txt
      supporting_text: it is unable to bind eIF4G (EIF4G1, EIF4G2 or EIF4G3),
- term:
    id: GO:0016281
    label: eukaryotic translation initiation factor 4F complex
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: part_of
  review:
    summary: >-
      Phylogenetic transfer from eIF4E. 4EHP is NOT a component of the productive eIF4F
      complex - it specifically lacks eIF4G binding and functions in distinct repressor
      complexes (4EHP-GIGYF2). This CC assignment is incorrect for 4EHP.
    action: REMOVE
    reason: >-
      4EHP cannot bind eIF4G and does not assemble into eIF4F; the annotation is an
      erroneous family-level transfer.
    supported_by:
    - reference_id: file:human/EIF4E2/EIF4E2-uniprot.txt
      supporting_text: it is unable to bind eIF4G (EIF4G1, EIF4G2 or EIF4G3),
- term:
    id: GO:0000932
    label: P-body
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  qualifier: located_in
  review:
    summary: >-
      P-body localization. Consistent with 4EHP's role in miRNA-mediated repression and
      mRNA storage/decay; corroborated by IDA.
    action: ACCEPT
    reason: >-
      4EHP localizes to P-bodies and acts there in miRNA silencing.
    supported_by:
    - reference_id: PMID:28487484
      supporting_text: Cap-binding protein 4EHP effects translation silencing by microRNAs.
- term:
    id: GO:0003723
    label: RNA binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: enables
  review:
    summary: >-
      Generic RNA binding (IEA). 4EHP binds the m7G cap of mRNAs; the more specific cap-
      binding MF is the informative term.
    action: KEEP_AS_NON_CORE
    reason: >-
      Correct but subsumed by the specific RNA 7-methylguanosine cap binding annotation.
    supported_by:
    - reference_id: PMID:17368478
      supporting_text: Structures of the human eIF4E homologous protein, h4EHP, in its m7GTP-bound and unliganded forms.
- term:
    id: GO:0003743
    label: translation initiation factor activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: enables
  review:
    summary: >-
      Electronic transfer. As with the IBA, 4EHP is a cap-binding repressor, not a
      productive initiation factor.
    action: MODIFY
    reason: >-
      4EHP does not promote initiation; a translation-regulator/repressor MF is correct.
    proposed_replacement_terms:
    - id: GO:0045182
      label: translation regulator activity
    supported_by:
    - reference_id: file:human/EIF4E2/EIF4E2-uniprot.txt
      supporting_text: it is unable to bind eIF4G (EIF4G1, EIF4G2 or EIF4G3),
- term:
    id: GO:0005737
    label: cytoplasm
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: located_in
  review:
    summary: >-
      Cytoplasmic localization (IEA). Consistent with 4EHP's cytosolic translation-
      repression activity.
    action: ACCEPT
    reason: >-
      4EHP is a cytoplasmic cap-binding protein; supported by direct evidence.
    supported_by:
    - reference_id: PMID:23991149
      supporting_text: Investigating the consequences of eIF4E2 (4EHP) interaction with 4E-transporter on its cellular distribution in HeLa cells.
- term:
    id: GO:0006413
    label: translational initiation
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: involved_in
  review:
    summary: >-
      Electronic transfer over-stating a positive initiation role.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      4EHP represses cap-dependent initiation; the positive 'translational initiation'
      involvement is misleading.
    supported_by:
    - reference_id: file:human/EIF4E2/EIF4E2-uniprot.txt
      supporting_text: it is unable to bind eIF4G (EIF4G1, EIF4G2 or EIF4G3),
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:15094042
  qualifier: enables
  review:
    summary: >-
      Generic IPI protein-binding annotation. Uninformative as a molecular function.
    action: KEEP_AS_NON_CORE
    reason: >-
      Records an interaction but the generic term is not elevated.
    supported_by:
    - reference_id: file:human/EIF4E2/EIF4E2-goa.tsv
      supporting_text: PMID:15094042
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:15161933
  qualifier: enables
  review:
    summary: >-
      Generic IPI protein-binding annotation from an mRNA-degradation interaction
      framework. Uninformative as a molecular function.
    action: KEEP_AS_NON_CORE
    reason: >-
      Records an interaction but the generic term is not elevated.
    supported_by:
    - reference_id: file:human/EIF4E2/EIF4E2-goa.tsv
      supporting_text: PMID:15161933
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:16189514
  qualifier: enables
  review:
    summary: >-
      Generic IPI protein-binding annotation. Uninformative as a molecular function.
    action: KEEP_AS_NON_CORE
    reason: >-
      Records an interaction but the generic term is not elevated.
    supported_by:
    - reference_id: file:human/EIF4E2/EIF4E2-goa.tsv
      supporting_text: PMID:16189514
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:19060904
  qualifier: enables
  review:
    summary: >-
      Generic IPI protein-binding annotation. Uninformative as a molecular function.
    action: KEEP_AS_NON_CORE
    reason: >-
      Records an interaction but the generic term is not elevated.
    supported_by:
    - reference_id: file:human/EIF4E2/EIF4E2-goa.tsv
      supporting_text: PMID:19060904
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:22678294
  qualifier: enables
  review:
    summary: >-
      Generic IPI protein-binding annotation. Uninformative as a molecular function.
    action: KEEP_AS_NON_CORE
    reason: >-
      Records an interaction but the generic term is not elevated.
    supported_by:
    - reference_id: file:human/EIF4E2/EIF4E2-goa.tsv
      supporting_text: PMID:22678294
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:25416956
  qualifier: enables
  review:
    summary: >-
      Generic protein-binding annotation from the HI-III human interactome (Y2H). Uninformative as a molecular function.
    action: KEEP_AS_NON_CORE
    reason: >-
      Large-scale interactome screen; no specific functional insight.
    supported_by:
    - reference_id: PMID:25416956
      supporting_text: A proteome-scale map of the human interactome network.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:25959826
  qualifier: enables
  review:
    summary: >-
      Generic IPI protein-binding annotation. Uninformative as a molecular function.
    action: KEEP_AS_NON_CORE
    reason: >-
      Records an interaction but the generic term is not elevated.
    supported_by:
    - reference_id: file:human/EIF4E2/EIF4E2-goa.tsv
      supporting_text: PMID:25959826
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:28514442
  qualifier: enables
  review:
    summary: >-
      Generic IPI protein-binding annotation. Uninformative as a molecular function.
    action: KEEP_AS_NON_CORE
    reason: >-
      Records an interaction but the generic term is not elevated.
    supported_by:
    - reference_id: file:human/EIF4E2/EIF4E2-goa.tsv
      supporting_text: PMID:28514442
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:31515488
  qualifier: enables
  review:
    summary: >-
      Generic IPI protein-binding annotation. Uninformative as a molecular function.
    action: KEEP_AS_NON_CORE
    reason: >-
      Records an interaction but the generic term is not elevated.
    supported_by:
    - reference_id: file:human/EIF4E2/EIF4E2-goa.tsv
      supporting_text: PMID:31515488
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:32814053
  qualifier: enables
  review:
    summary: >-
      Generic protein-binding annotation from a neurodegenerative-disease interactome mapping study. Uninformative as a molecular function.
    action: KEEP_AS_NON_CORE
    reason: >-
      High-throughput interactome dataset; no specific functional insight.
    supported_by:
    - reference_id: PMID:32814053
      supporting_text: Interactome Mapping Provides a Network of Neurodegenerative Disease Proteins and Uncovers Widespread Protein Aggregation in Affected Brains.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:33961781
  qualifier: enables
  review:
    summary: >-
      Generic protein-binding annotation from the BioPlex interactome. Uninformative as a
      molecular function.
    action: KEEP_AS_NON_CORE
    reason: >-
      High-throughput AP-MS interactome; the meaningful GIGYF1/GIGYF2 interactions are
      captured separately.
    supported_by:
    - reference_id: PMID:33961781
      supporting_text: Dual proteome-scale networks reveal cell-specific remodeling of the human interactome.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:35271311
  qualifier: enables
  review:
    summary: >-
      Generic protein-binding annotation from a proximity-biotinylation map. Uninformative as a molecular function.
    action: KEEP_AS_NON_CORE
    reason: >-
      High-throughput proximity-labeling dataset; no specific functional insight.
    supported_by:
    - reference_id: PMID:35271311
      supporting_text: >-
        We combined genome engineering, confocal live-cell imaging, mass spectrometry and data
        science to systematically map the localization and interactions of human proteins.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:40205054
  qualifier: enables
  review:
    summary: >-
      Generic IPI protein-binding annotation. Uninformative as a molecular function.
    action: KEEP_AS_NON_CORE
    reason: >-
      Records an interaction but the generic term is not elevated.
    supported_by:
    - reference_id: file:human/EIF4E2/EIF4E2-goa.tsv
      supporting_text: PMID:40205054
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: IDA
  original_reference_id: GO_REF:0000052
  qualifier: located_in
  review:
    summary: >-
      Direct cytosol localization. Consistent with 4EHP's cytosolic function.
    action: ACCEPT
    reason: >-
      Cytosolic localization is experimentally supported.
    supported_by:
    - reference_id: PMID:23991149
      supporting_text: Investigating the consequences of eIF4E2 (4EHP) interaction with 4E-transporter on its cellular distribution in HeLa cells.
- term:
    id: GO:1990261
    label: pre-mRNA catabolic process
  evidence_type: NAS
  original_reference_id: PMID:33053355
  qualifier: involved_in
  review:
    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.
    action: MODIFY
    reason: >-
      The complex triggers co-translational decay of mature mRNAs, not pre-mRNA turnover.
    proposed_replacement_terms:
    - id: GO:0000956
      label: nuclear-transcribed mRNA catabolic process
    supported_by:
    - reference_id: PMID:33053355
      supporting_text: 4EHP and GIGYF1/2 Mediate Translation-Coupled Messenger RNA Decay.
- term:
    id: GO:0098808
    label: mRNA cap binding
  evidence_type: IDA
  original_reference_id: PMID:17368478
  qualifier: enables
  review:
    summary: >-
      Direct evidence for mRNA cap binding (m7GTP-bound crystal structure). Core MF.
    action: ACCEPT
    reason: >-
      Structural and biochemical data directly demonstrate cap binding by 4EHP.
    supported_by:
    - reference_id: PMID:17368478
      supporting_text: Structures of the human eIF4E homologous protein, h4EHP, in its m7GTP-bound and unliganded forms.
- term:
    id: GO:0000340
    label: RNA 7-methylguanosine cap binding
  evidence_type: IDA
  original_reference_id: PMID:35878012
  qualifier: enables
  review:
    summary: >-
      Direct evidence for m7G cap binding in the context of IFNB1 repression. Core MF.
    action: ACCEPT
    reason: >-
      4EHP cap binding is required for its repression of target mRNAs including IFNB1.
    supported_by:
    - reference_id: PMID:35878012
      supporting_text: SARS-CoV-2 impairs interferon production via NSP2-induced repression of mRNA translation.
- term:
    id: GO:0045947
    label: negative regulation of translational initiation
  evidence_type: IDA
  original_reference_id: PMID:32726578
  qualifier: involved_in
  review:
    summary: >-
      Core function: 4EHP (with GIGYF2) inhibits translation initiation on defective/
      ribosome-stalling mRNAs as part of RQC.
    action: ACCEPT
    reason: >-
      Direct evidence places 4EHP/GIGYF2 as inhibitors of initiation on faulty messages.
    supported_by:
    - reference_id: PMID:32726578
      supporting_text: GIGYF2 and 4EHP Inhibit Translation Initiation of Defective Messenger RNAs to Assist Ribosome-Associated Quality Control.
- term:
    id: GO:0045947
    label: negative regulation of translational initiation
  evidence_type: IDA
  original_reference_id: PMID:35878012
  qualifier: involved_in
  review:
    summary: >-
      4EHP/GIGYF2 repress IFNB1 translation initiation; co-opted by SARS-CoV-2 nsp2.
      Supports the core repressor function.
    action: ACCEPT
    reason: >-
      Direct evidence of 4EHP-mediated repression of IFNB1 translation.
    supported_by:
    - reference_id: PMID:35878012
      supporting_text: SARS-CoV-2 impairs interferon production via NSP2-induced repression of mRNA translation.
- term:
    id: GO:0060339
    label: negative regulation of type I interferon-mediated signaling pathway
  evidence_type: IDA
  original_reference_id: PMID:35878012
  qualifier: involved_in
  review:
    summary: >-
      4EHP/GIGYF2 repress IFNB1 (type I IFN) translation. A genuine, context-specific role
      rather than the core, ubiquitous function.
    action: KEEP_AS_NON_CORE
    reason: >-
      The IFN-repression role is a specific outcome of 4EHP's general repression activity on
      IFNB1 mRNA, exploited during SARS-CoV-2 infection.
    supported_by:
    - reference_id: PMID:35878012
      supporting_text: SARS-CoV-2 impairs interferon production via NSP2-induced repression of mRNA translation.
- term:
    id: GO:0072344
    label: rescue of stalled cytosolic ribosome
  evidence_type: IDA
  original_reference_id: PMID:32726578
  qualifier: involved_in
  review:
    summary: >-
      4EHP (with GIGYF2) participates in ribosome-associated quality control by suppressing
      new initiation on ribosome-stalling mRNAs. Core RQC function.
    action: ACCEPT
    reason: >-
      Direct evidence places 4EHP/GIGYF2 in the RQC response acting in parallel with
      degradation of the stalled nascent chain.
    supported_by:
    - reference_id: file:human/EIF4E2/EIF4E2-uniprot.txt
      supporting_text: sequestering the mRNA cap, blocking
- term:
    id: GO:0035278
    label: miRNA-mediated gene silencing by inhibition of translation
  evidence_type: IDA
  original_reference_id: PMID:28487484
  qualifier: acts_upstream_of_positive_effect
  review:
    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.
    action: ACCEPT
    reason: >-
      Direct evidence that 4EHP cap binding contributes to miRNA-mediated translational
      silencing.
    supported_by:
    - reference_id: PMID:28487484
      supporting_text: 4EHP is an integral component of the miRNA-mediated silencing machinery.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:31439631
  qualifier: enables
  review:
    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.
    action: KEEP_AS_NON_CORE
    reason: >-
      The 4EHP-GIGYF interaction is the basis of the repressor complex, but the generic
      term is not elevated; the cap-binding MF and repression BP capture 4EHP's function.
    supported_by:
    - reference_id: PMID:31439631
      supporting_text: Molecular basis for GIGYF-Me31B complex assembly in 4EHP-mediated translational repression.
- term:
    id: GO:0000932
    label: P-body
  evidence_type: IDA
  original_reference_id: PMID:23991149
  qualifier: located_in
  review:
    summary: >-
      Direct P-body localization, consistent with 4EHP's role in repressed-mRNP/miRNA
      silencing.
    action: ACCEPT
    reason: >-
      4EHP localizes to P-bodies, consistent with its repression function.
    supported_by:
    - reference_id: PMID:23991149
      supporting_text: Investigating the consequences of eIF4E2 (4EHP) interaction with 4E-transporter on its cellular distribution in HeLa cells.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:23991149
  qualifier: enables
  review:
    summary: >-
      IPI annotation for the 4EHP-4E-T (EIF4ENIF1) interaction, which influences 4EHP's
      cellular distribution. Real but the generic term is uninformative.
    action: KEEP_AS_NON_CORE
    reason: >-
      Records the 4E-T interaction relevant to localization/silencing, but 'protein binding'
      is not elevated.
    supported_by:
    - reference_id: PMID:23991149
      supporting_text: Investigating the consequences of eIF4E2 (4EHP) interaction with 4E-transporter on its cellular distribution in HeLa cells.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:28487484
  qualifier: enables
  review:
    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.
    action: KEEP_AS_NON_CORE
    reason: >-
      Records silencing-machinery interactions; the generic term is not elevated.
    supported_by:
    - reference_id: PMID:28487484
      supporting_text: 4EHP is an integral component of the miRNA-mediated silencing machinery.
- term:
    id: GO:0005737
    label: cytoplasm
  evidence_type: IDA
  original_reference_id: PMID:23991149
  qualifier: located_in
  review:
    summary: >-
      Direct cytoplasmic localization.
    action: ACCEPT
    reason: >-
      4EHP is a cytoplasmic protein, supported by direct evidence.
    supported_by:
    - reference_id: PMID:23991149
      supporting_text: Investigating the consequences of eIF4E2 (4EHP) interaction with 4E-transporter on its cellular distribution in HeLa cells.
- term:
    id: GO:0003723
    label: RNA binding
  evidence_type: HDA
  original_reference_id: PMID:22681889
  qualifier: enables
  review:
    summary: >-
      RNA binding from a proteome-wide mRNA-interactome capture study. Subsumed by the
      specific cap-binding MF.
    action: KEEP_AS_NON_CORE
    reason: >-
      Correct but less informative than RNA 7-methylguanosine cap binding.
    supported_by:
    - reference_id: file:human/EIF4E2/EIF4E2-goa.tsv
      supporting_text: PMID:22681889
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-1678842
  qualifier: located_in
  review:
    summary: >-
      Cytosol localization (Reactome TAS). Consistent with 4EHP's cytosolic function.
    action: ACCEPT
    reason: >-
      Cytosolic localization is well supported.
    supported_by:
    - reference_id: PMID:23991149
      supporting_text: Investigating the consequences of eIF4E2 (4EHP) interaction with 4E-transporter on its cellular distribution in HeLa cells.
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-1678843
  qualifier: located_in
  review:
    summary: >-
      Duplicate cytosol localization (Reactome TAS).
    action: ACCEPT
    reason: >-
      Cytosolic localization is well supported.
    supported_by:
    - reference_id: PMID:23991149
      supporting_text: Investigating the consequences of eIF4E2 (4EHP) interaction with 4E-transporter on its cellular distribution in HeLa cells.
- term:
    id: GO:0017148
    label: negative regulation of translation
  evidence_type: IMP
  original_reference_id: PMID:22751931
  qualifier: acts_upstream_of_or_within
  review:
    summary: >-
      Genetic/biochemical evidence that the 4EHP-GIGYF2 complex represses translation;
      disruption increases translation and causes perinatal lethality in mice. Core.
    action: ACCEPT
    reason: >-
      Disruption of the m4EHP-GIGYF2 complex increases translation, directly demonstrating
      4EHP's negative regulation of translation.
    supported_by:
    - reference_id: PMID:22751931
      supporting_text: A novel 4EHP-GIGYF2 translational repressor complex is essential for mammalian development.
- term:
    id: GO:0031625
    label: ubiquitin protein ligase binding
  evidence_type: IPI
  original_reference_id: PMID:14623119
  qualifier: enables
  review:
    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).
    action: ACCEPT
    reason: >-
      Direct evidence that HHARI/ARIH1 (a ubiquitin protein ligase) interacts with and
      ubiquitylates 4EHP.
    supported_by:
    - reference_id: PMID:14623119
      supporting_text: Human homologue of ariadne promotes the ubiquitylation of translation initiation factor 4E homologous protein, 4EHP.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:17368478
  qualifier: enables
  review:
    summary: >-
      Generic protein-binding annotation from the structural/cap-binding study. The
      informative MF (cap binding) is captured separately.
    action: KEEP_AS_NON_CORE
    reason: >-
      Records interactions in the structural study; the generic term is not elevated.
    supported_by:
    - reference_id: PMID:17368478
      supporting_text: Structures of the human eIF4E homologous protein, h4EHP, in its m7GTP-bound and unliganded forms.
- term:
    id: GO:0000339
    label: RNA cap binding
  evidence_type: TAS
  original_reference_id: PMID:9582349
  qualifier: enables
  review:
    summary: >-
      Cap binding (TAS, original characterization). 4EHP is an eIF4E-related cap-binding
      protein. Core MF.
    action: ACCEPT
    reason: >-
      The original cloning/characterization established 4EHP as a cap-binding protein.
    supported_by:
    - reference_id: PMID:9582349
      supporting_text: Cloning and characterization of 4EHP, a novel mammalian eIF4E-related cap-binding protein.
- term:
    id: GO:0008135
    label: translation factor activity, RNA binding
  evidence_type: TAS
  original_reference_id: PMID:9582349
  qualifier: enables
  review:
    summary: >-
      Broad 'translation factor activity, RNA binding' term applied to 4EHP. Given that
      4EHP acts as a translational repressor rather than a productive factor, a repressor/
      regulator MF is more accurate, but the cap-binding RNA activity is genuine.
    action: KEEP_AS_NON_CORE
    reason: >-
      4EHP is an RNA(cap)-binding translation regulator; this broad factor MF is acceptable
      but less informative than the specific cap-binding MF and the negative-regulation BP.
    supported_by:
    - reference_id: PMID:9582349
      supporting_text: Cloning and characterization of 4EHP, a novel mammalian eIF4E-related cap-binding protein.
core_functions:
- description: >-
    4EHP recognizes and binds the m7G mRNA 5' cap. Because it cannot recruit eIF4G, cap
    binding by 4EHP competes with eIF4E and blocks eIF4F assembly, the molecular basis of
    its translational-repressor activity.
  molecular_function:
    id: GO:0000340
    label: RNA 7-methylguanosine cap binding
  locations:
  - id: GO:0005829
    label: cytosol
  - id: GO:0000932
    label: P-body
  supported_by:
  - reference_id: PMID:17368478
    supporting_text: Structures of the human eIF4E homologous protein, h4EHP, in its m7GTP-bound and unliganded forms.
- description: >-
    As the cap-binding core of the 4EHP-GIGYF2 module (with GIGYF1/2, ZNF598 and DDX6) and of
    miRNA/CCR4-NOT silencing, 4EHP represses cap-dependent translation initiation of specific
    mRNAs, including ribosome-stalling messages in ribosome-associated quality control.
  molecular_function:
    id: GO:0000340
    label: RNA 7-methylguanosine cap binding
  locations:
  - id: GO:0005829
    label: cytosol
  supported_by:
  - reference_id: PMID:32726578
    supporting_text: GIGYF2 and 4EHP Inhibit Translation Initiation of Defective Messenger RNAs to Assist Ribosome-Associated Quality Control.
  directly_involved_in:
  - id: GO:0045947
    label: negative regulation of translational initiation
proposed_new_terms: []
suggested_questions:
- question: Under what conditions, if any, does 4EHP support (rather than repress) cap-dependent translation of specific mRNAs, and how is the switch between repressor and any positive role regulated?
- question: How is 4EHP partitioned among its distinct repressor complexes (GIGYF1/2-RQC, 4E-T/CCR4-NOT miRNA silencing), and does ARIH1-mediated ubiquitylation regulate this?
suggested_experiments:
- description: Cap-binding separation-of-function mutants of 4EHP tested in RQC reporter assays versus miRNA-silencing reporters to dissect the contributions of cap binding to each pathway.
- description: Quantitative proteomics of 4EHP complexes (GIGYF1/2, ZNF598, 4E-T, CCR4-NOT) across conditions to map context-dependent complex assembly and target mRNA selection.
references:
- id: GO_REF:0000002
  title: Gene Ontology annotation through association of InterPro records with GO terms
  findings: []
- id: GO_REF:0000033
  title: Annotation inferences using phylogenetic trees
  findings: []
- id: GO_REF:0000044
  title: Gene Ontology annotation based on UniProtKB/Swiss-Prot Subcellular Location vocabulary mapping
  findings: []
- id: GO_REF:0000052
  title: Gene Ontology annotation based on curation of immunofluorescence data
  findings: []
- id: GO_REF:0000120
  title: Combined Automated Annotation using Multiple IEA Methods
  findings: []
- id: PMID:14623119
  title: Human homologue of ariadne promotes the ubiquitylation of translation initiation factor 4E homologous protein, 4EHP.
  findings:
  - statement: The RBR E3 ligase HHARI/ARIH1 interacts with 4EHP and promotes its polyubiquitylation.
    reference_section_type: ABSTRACT
- id: PMID:15094042
  title: 'Characterizing the interaction of the mammalian eIF4E-related protein 4EHP with 4E-BP1.'
  findings: []
- id: PMID:15161933
  title: Comprehensive proteomic analysis of interphase and mitotic 14-3-3-binding proteins.
  findings: []
- id: PMID:16189514
  title: Towards a proteome-scale map of the human protein-protein interaction network.
  findings: []
- id: PMID:17368478
  title: Structures of the human eIF4E homologous protein, h4EHP, in its m7GTP-bound and unliganded forms.
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: "Cached publications/PMID_17368478.md title matches YAML; crystal structures of h4EHP in m7GTP-bound/unliganded forms establish the core MF (m7G cap binding, GO:0000340). GOA also anchors this PMID to cap binding (GO:0098808, IDA)."
  findings:
  - statement: 4EHP binds the m7G cap; crystal structures resolve 4EHP in m7GTP-bound and unliganded forms.
    reference_section_type: ABSTRACT
- id: PMID:19060904
  title: An empirical framework for binary interactome mapping.
  findings: []
- id: PMID:22678294
  title: 'An oxygen-regulated switch in the protein synthesis machinery.'
  findings: []
- id: PMID:22681889
  title: The mRNA-bound proteome and its global occupancy profile on protein-coding transcripts.
  findings: []
- id: PMID:22751931
  title: A novel 4EHP-GIGYF2 translational repressor complex is essential for mammalian development.
  findings:
  - statement: Disruption of the m4EHP-GIGYF2 complex increases translation and causes perinatal lethality in mice, demonstrating 4EHP's repressor function.
    reference_section_type: ABSTRACT
- id: PMID:23991149
  title: Investigating the consequences of eIF4E2 (4EHP) interaction with 4E-transporter on its cellular distribution in HeLa cells.
  findings:
  - statement: 4EHP interacts with 4E-T (EIF4ENIF1), which influences its cytoplasmic and P-body distribution.
    reference_section_type: ABSTRACT
- id: PMID:25416956
  title: A proteome-scale map of the human interactome network.
  findings: []
- id: PMID:25959826
  title: Quantitative interaction proteomics of neurodegenerative disease proteins.
  findings: []
- id: PMID:28487484
  title: Cap-binding protein 4EHP effects translation silencing by microRNAs.
  findings:
  - statement: 4EHP is an integral component of the miRNA-mediated silencing machinery; its cap-binding activity contributes to translational silencing of miRNA targets via 4E-T and the CCR4-NOT complex.
    reference_section_type: ABSTRACT
- id: PMID:28514442
  title: Architecture of the human interactome defines protein communities and disease networks.
  findings: []
- id: PMID:31439631
  title: Molecular basis for GIGYF-Me31B complex assembly in 4EHP-mediated translational repression.
  findings:
  - statement: 4EHP assembles with GIGYF and DDX6 into a translational-repressor complex; GIGYF binds 4EHP via a dedicated 4EHP-binding motif.
    reference_section_type: RESULTS
- id: PMID:31515488
  title: Extensive disruption of protein interactions by genetic variants across the allele frequency spectrum in human populations.
  findings: []
- id: PMID:32726578
  title: GIGYF2 and 4EHP Inhibit Translation Initiation of Defective Messenger RNAs to Assist Ribosome-Associated Quality Control.
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: "Cached publications/PMID_32726578.md title matches YAML; establishes 4EHP/GIGYF2 repression of translation initiation on defective mRNAs in RQC, the core BP. GOA anchors this PMID to GO:0045947 (negative regulation of translational initiation, IDA)."
  findings:
  - statement: 4EHP and GIGYF2 inhibit translation initiation on defective, ribosome-stalling mRNAs as a negative-feedback RQC mechanism.
    reference_section_type: ABSTRACT
- id: PMID:32814053
  title: Interactome Mapping Provides a Network of Neurodegenerative Disease Proteins and Uncovers Widespread Protein Aggregation in Affected Brains.
  findings: []
- id: PMID:33053355
  title: 4EHP and GIGYF1/2 Mediate Translation-Coupled Messenger RNA Decay.
  findings:
  - statement: 4EHP-GIGYF1/2 complexes trigger co-translational mRNA decay of transcripts that experience ribosome pausing.
    reference_section_type: ABSTRACT
- id: PMID:33961781
  title: Dual proteome-scale networks reveal cell-specific remodeling of the human interactome.
  findings: []
- id: PMID:35271311
  title: 'OpenCell: Endogenous tagging for the cartography of human cellular organization.'
  findings: []
- id: PMID:35878012
  title: SARS-CoV-2 impairs interferon production via NSP2-induced repression of mRNA translation.
  findings:
  - statement: SARS-CoV-2 nsp2 enhances GIGYF2-EIF4E2 association to repress IFNB1 translation, dampening the type I interferon response; 4EHP cap binding is required.
    reference_section_type: ABSTRACT
- id: PMID:40205054
  title: Multimodal cell maps as a foundation for structural and functional genomics.
  findings: []
- id: PMID:9582349
  title: Cloning and characterization of 4EHP, a novel mammalian eIF4E-related cap-binding protein.
  findings:
  - statement: 4EHP was cloned and characterized as a novel mammalian eIF4E-related cap- binding protein.
    reference_section_type: ABSTRACT
- id: Reactome:R-HSA-1678842
  title: Reactome pathway annotation (cytosol localization)
  findings: []
- id: Reactome:R-HSA-1678843
  title: Reactome pathway annotation (cytosol localization)
  findings: []
- id: file:human/EIF4E2/EIF4E2-uniprot.txt
  title: UniProt entry O60573 (IF4E2_HUMAN)
  findings: []
- id: file:human/EIF4E2/EIF4E2-goa.tsv
  title: GOA annotations for EIF4E2
  findings: []