EIF4E2

UniProt ID: O60573
Organism: Homo sapiens
Review Status: COMPLETE
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Gene 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 Review

GO Term Evidence Action Reason
GO:0000340 RNA 7-methylguanosine cap binding
IBA
GO_REF:0000033 		ACCEPT
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.
Supporting Evidence:
PMID:17368478
Structures of the human eIF4E homologous protein, h4EHP, in its m7GTP-bound and unliganded forms.
GO:0003743 translation initiation factor activity
IBA
GO_REF:0000033 		MODIFY
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.
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 replacements: translation regulator activity
Supporting Evidence:
file:human/EIF4E2/EIF4E2-uniprot.txt
it is unable to bind eIF4G (EIF4G1, EIF4G2 or EIF4G3),
GO:0006413 translational initiation
IBA
GO_REF:0000033 		MARK AS OVER ANNOTATED
Summary: Phylogenetic transfer. 4EHP participates in initiation only as a repressor; the generic 'translational initiation' over-states a positive role.
Reason: 4EHP represses, rather than mediates, cap-dependent initiation; the specific role is better captured by negative regulation of translational initiation.
Supporting Evidence:
file:human/EIF4E2/EIF4E2-uniprot.txt
it is unable to bind eIF4G (EIF4G1, EIF4G2 or EIF4G3),
GO:0016281 eukaryotic translation initiation factor 4F complex
IBA
GO_REF:0000033 		REMOVE
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.
Reason: 4EHP cannot bind eIF4G and does not assemble into eIF4F; the annotation is an erroneous family-level transfer.
Supporting Evidence:
file:human/EIF4E2/EIF4E2-uniprot.txt
it is unable to bind eIF4G (EIF4G1, EIF4G2 or EIF4G3),
GO:0000932 P-body
IEA
GO_REF:0000044 		ACCEPT
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.
Supporting Evidence:
PMID:28487484
Cap-binding protein 4EHP effects translation silencing by microRNAs.
GO:0003723 RNA binding
IEA
GO_REF:0000002 		KEEP AS NON CORE
Summary: Generic RNA binding (IEA). 4EHP binds the m7G cap of mRNAs; the more specific cap- binding MF is the informative term.
Reason: Correct but subsumed by the specific RNA 7-methylguanosine cap binding annotation.
Supporting Evidence:
PMID:17368478
Structures of the human eIF4E homologous protein, h4EHP, in its m7GTP-bound and unliganded forms.
GO:0003743 translation initiation factor activity
IEA
GO_REF:0000002 		MODIFY
Summary: Electronic transfer. As with the IBA, 4EHP is a cap-binding repressor, not a productive initiation factor.
Reason: 4EHP does not promote initiation; a translation-regulator/repressor MF is correct.
Proposed replacements: translation regulator activity
Supporting Evidence:
file:human/EIF4E2/EIF4E2-uniprot.txt
it is unable to bind eIF4G (EIF4G1, EIF4G2 or EIF4G3),
GO:0005737 cytoplasm
IEA
GO_REF:0000120 		ACCEPT
Summary: Cytoplasmic localization (IEA). Consistent with 4EHP's cytosolic translation- repression activity.
Reason: 4EHP is a cytoplasmic cap-binding protein; supported by direct evidence.
Supporting Evidence:
PMID:23991149
Investigating the consequences of eIF4E2 (4EHP) interaction with 4E-transporter on its cellular distribution in HeLa cells.
GO:0006413 translational initiation
IEA
GO_REF:0000002 		MARK AS OVER ANNOTATED
Summary: Electronic transfer over-stating a positive initiation role.
Reason: 4EHP represses cap-dependent initiation; the positive 'translational initiation' involvement is misleading.
Supporting Evidence:
file:human/EIF4E2/EIF4E2-uniprot.txt
it is unable to bind eIF4G (EIF4G1, EIF4G2 or EIF4G3),
GO:0005515 protein binding
IPI
PMID:15094042
Characterizing the interaction of the mammalian eIF4E-relate... 		KEEP AS NON CORE
Summary: Generic IPI protein-binding annotation. Uninformative as a molecular function.
Reason: Records an interaction but the generic term is not elevated.
Supporting Evidence:
file:human/EIF4E2/EIF4E2-goa.tsv
PMID:15094042
GO:0005515 protein binding
IPI
PMID:15161933
Comprehensive proteomic analysis of interphase and mitotic 1... 		KEEP AS NON CORE
Summary: Generic IPI protein-binding annotation from an mRNA-degradation interaction framework. Uninformative as a molecular function.
Reason: Records an interaction but the generic term is not elevated.
Supporting Evidence:
file:human/EIF4E2/EIF4E2-goa.tsv
PMID:15161933
GO:0005515 protein binding
IPI
PMID:16189514
Towards a proteome-scale map of the human protein-protein in... 		KEEP AS NON CORE
Summary: Generic IPI protein-binding annotation. Uninformative as a molecular function.
Reason: Records an interaction but the generic term is not elevated.
Supporting Evidence:
file:human/EIF4E2/EIF4E2-goa.tsv
PMID:16189514
GO:0005515 protein binding
IPI
PMID:19060904
An empirical framework for binary interactome mapping. 		KEEP AS NON CORE
Summary: Generic IPI protein-binding annotation. Uninformative as a molecular function.
Reason: Records an interaction but the generic term is not elevated.
Supporting Evidence:
file:human/EIF4E2/EIF4E2-goa.tsv
PMID:19060904
GO:0005515 protein binding
IPI
PMID:22678294
An oxygen-regulated switch in the protein synthesis machiner... 		KEEP AS NON CORE
Summary: Generic IPI protein-binding annotation. Uninformative as a molecular function.
Reason: Records an interaction but the generic term is not elevated.
Supporting Evidence:
file:human/EIF4E2/EIF4E2-goa.tsv
PMID:22678294
GO:0005515 protein binding
IPI
PMID:25416956
A proteome-scale map of the human interactome network. 		KEEP AS NON CORE
Summary: Generic protein-binding annotation from the HI-III human interactome (Y2H). Uninformative as a molecular function.
Reason: Large-scale interactome screen; no specific functional insight.
Supporting Evidence:
PMID:25416956
A proteome-scale map of the human interactome network.
GO:0005515 protein binding
IPI
PMID:25959826
Quantitative interaction proteomics of neurodegenerative dis... 		KEEP AS NON CORE
Summary: Generic IPI protein-binding annotation. Uninformative as a molecular function.
Reason: Records an interaction but the generic term is not elevated.
Supporting Evidence:
file:human/EIF4E2/EIF4E2-goa.tsv
PMID:25959826
GO:0005515 protein binding
IPI
PMID:28514442
Architecture of the human interactome defines protein commun... 		KEEP AS NON CORE
Summary: Generic IPI protein-binding annotation. Uninformative as a molecular function.
Reason: Records an interaction but the generic term is not elevated.
Supporting Evidence:
file:human/EIF4E2/EIF4E2-goa.tsv
PMID:28514442
GO:0005515 protein binding
IPI
PMID:31515488
Extensive disruption of protein interactions by genetic vari... 		KEEP AS NON CORE
Summary: Generic IPI protein-binding annotation. Uninformative as a molecular function.
Reason: Records an interaction but the generic term is not elevated.
Supporting Evidence:
file:human/EIF4E2/EIF4E2-goa.tsv
PMID:31515488
GO:0005515 protein binding
IPI
PMID:32814053
Interactome Mapping Provides a Network of Neurodegenerative ... 		KEEP AS NON CORE
Summary: Generic protein-binding annotation from a neurodegenerative-disease interactome mapping study. Uninformative as a molecular function.
Reason: High-throughput interactome dataset; no specific functional insight.
Supporting Evidence:
PMID:32814053
Interactome Mapping Provides a Network of Neurodegenerative Disease Proteins and Uncovers Widespread Protein Aggregation in Affected Brains.
GO:0005515 protein binding
IPI
PMID:33961781
Dual proteome-scale networks reveal cell-specific remodeling... 		KEEP AS NON CORE
Summary: Generic protein-binding annotation from the BioPlex interactome. Uninformative as a molecular function.
Reason: High-throughput AP-MS interactome; the meaningful GIGYF1/GIGYF2 interactions are captured separately.
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... 		KEEP AS NON CORE
Summary: Generic protein-binding annotation from a proximity-biotinylation map. Uninformative as a molecular function.
Reason: High-throughput proximity-labeling dataset; no specific functional insight.
Supporting Evidence:
PMID:35271311
We combined genome engineering, confocal live-cell imaging, mass spectrometry and data science to systematically map the localization and interactions of human proteins.
GO:0005515 protein binding
IPI
PMID:40205054
Multimodal cell maps as a foundation for structural and func... 		KEEP AS NON CORE
Summary: Generic IPI protein-binding annotation. Uninformative as a molecular function.
Reason: Records an interaction but the generic term is not elevated.
Supporting Evidence:
file:human/EIF4E2/EIF4E2-goa.tsv
PMID:40205054
GO:0005829 cytosol
IDA
GO_REF:0000052 		ACCEPT
Summary: Direct cytosol localization. Consistent with 4EHP's cytosolic function.
Reason: Cytosolic localization is experimentally supported.
Supporting Evidence:
PMID:23991149
Investigating the consequences of eIF4E2 (4EHP) interaction with 4E-transporter on its cellular distribution in HeLa cells.
GO:1990261 pre-mRNA catabolic process
NAS
PMID:33053355
4EHP and GIGYF1/2 Mediate Translation-Coupled Messenger RNA ... 		MODIFY
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.
Supporting Evidence:
PMID:33053355
4EHP and GIGYF1/2 Mediate Translation-Coupled Messenger RNA Decay.
GO:0098808 mRNA cap binding
IDA
PMID:17368478
Structures of the human eIF4E homologous protein, h4EHP, in ... 		ACCEPT
Summary: Direct evidence for mRNA cap binding (m7GTP-bound crystal structure). Core MF.
Reason: Structural and biochemical data directly demonstrate cap binding by 4EHP.
Supporting Evidence:
PMID:17368478
Structures of the human eIF4E homologous protein, h4EHP, in its m7GTP-bound and unliganded forms.
GO:0000340 RNA 7-methylguanosine cap binding
IDA
PMID:35878012
SARS-CoV-2 impairs interferon production via NSP2-induced re... 		ACCEPT
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.
Supporting Evidence:
PMID:35878012
SARS-CoV-2 impairs interferon production via NSP2-induced repression of mRNA translation.
GO:0045947 negative regulation of translational initiation
IDA
PMID:32726578
GIGYF2 and 4EHP Inhibit Translation Initiation of Defective ... 		ACCEPT
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.
Supporting Evidence:
PMID:32726578
GIGYF2 and 4EHP Inhibit Translation Initiation of Defective Messenger RNAs to Assist Ribosome-Associated Quality Control.
GO:0045947 negative regulation of translational initiation
IDA
PMID:35878012
SARS-CoV-2 impairs interferon production via NSP2-induced re... 		ACCEPT
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.
Supporting Evidence:
PMID:35878012
SARS-CoV-2 impairs interferon production via NSP2-induced repression of mRNA translation.
GO:0060339 negative regulation of type I interferon-mediated signaling pathway
IDA
PMID:35878012
SARS-CoV-2 impairs interferon production via NSP2-induced re... 		KEEP AS NON CORE
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.
Supporting Evidence:
PMID:35878012
SARS-CoV-2 impairs interferon production via NSP2-induced repression of mRNA translation.
GO:0072344 rescue of stalled cytosolic ribosome
IDA
PMID:32726578
GIGYF2 and 4EHP Inhibit Translation Initiation of Defective ... 		ACCEPT
Summary: 4EHP (with GIGYF2) participates in ribosome-associated quality control by suppressing new initiation on ribosome-stalling mRNAs. Core RQC function.
Reason: Direct evidence places 4EHP/GIGYF2 in the RQC response acting in parallel with degradation of the stalled nascent chain.
Supporting Evidence:
file:human/EIF4E2/EIF4E2-uniprot.txt
sequestering the mRNA cap, blocking
GO:0035278 miRNA-mediated gene silencing by inhibition of translation
IDA
PMID:28487484
Cap-binding protein 4EHP effects translation silencing by mi... 		ACCEPT
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.
Supporting Evidence:
PMID:28487484
4EHP is an integral component of the miRNA-mediated silencing machinery.
GO:0005515 protein binding
IPI
PMID:31439631
Molecular basis for GIGYF-Me31B complex assembly in 4EHP-med... 		KEEP AS NON CORE
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: 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.
Supporting Evidence:
PMID:31439631
Molecular basis for GIGYF-Me31B complex assembly in 4EHP-mediated translational repression.
GO:0000932 P-body
IDA
PMID:23991149
Investigating the consequences of eIF4E2 (4EHP) interaction ... 		ACCEPT
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.
Supporting Evidence:
PMID:23991149
Investigating the consequences of eIF4E2 (4EHP) interaction with 4E-transporter on its cellular distribution in HeLa cells.
GO:0005515 protein binding
IPI
PMID:23991149
Investigating the consequences of eIF4E2 (4EHP) interaction ... 		KEEP AS NON CORE
Summary: IPI annotation for the 4EHP-4E-T (EIF4ENIF1) interaction, which influences 4EHP's cellular distribution. Real but the generic term is uninformative.
Reason: Records the 4E-T interaction relevant to localization/silencing, but 'protein binding' is not elevated.
Supporting Evidence:
PMID:23991149
Investigating the consequences of eIF4E2 (4EHP) interaction with 4E-transporter on its cellular distribution in HeLa cells.
GO:0005515 protein binding
IPI
PMID:28487484
Cap-binding protein 4EHP effects translation silencing by mi... 		KEEP AS NON CORE
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: Records silencing-machinery interactions; the generic term is not elevated.
Supporting Evidence:
PMID:28487484
4EHP is an integral component of the miRNA-mediated silencing machinery.
GO:0005737 cytoplasm
IDA
PMID:23991149
Investigating the consequences of eIF4E2 (4EHP) interaction ... 		ACCEPT
Summary: Direct cytoplasmic localization.
Reason: 4EHP is a cytoplasmic protein, supported by direct evidence.
Supporting Evidence:
PMID:23991149
Investigating the consequences of eIF4E2 (4EHP) interaction with 4E-transporter on its cellular distribution in HeLa cells.
GO:0003723 RNA binding
HDA
PMID:22681889
The mRNA-bound proteome and its global occupancy profile on ... 		KEEP AS NON CORE
Summary: RNA binding from a proteome-wide mRNA-interactome capture study. Subsumed by the specific cap-binding MF.
Reason: Correct but less informative than RNA 7-methylguanosine cap binding.
Supporting Evidence:
file:human/EIF4E2/EIF4E2-goa.tsv
PMID:22681889
GO:0005829 cytosol
TAS
Reactome:R-HSA-1678842 		ACCEPT
Summary: Cytosol localization (Reactome TAS). Consistent with 4EHP's cytosolic function.
Reason: Cytosolic localization is well supported.
Supporting Evidence:
PMID:23991149
Investigating the consequences of eIF4E2 (4EHP) interaction with 4E-transporter on its cellular distribution in HeLa cells.
GO:0005829 cytosol
TAS
Reactome:R-HSA-1678843 		ACCEPT
Summary: Duplicate cytosol localization (Reactome TAS).
Reason: Cytosolic localization is well supported.
Supporting Evidence:
PMID:23991149
Investigating the consequences of eIF4E2 (4EHP) interaction with 4E-transporter on its cellular distribution in HeLa cells.
GO:0017148 negative regulation of translation
IMP
PMID:22751931
A novel 4EHP-GIGYF2 translational repressor complex is essen... 		ACCEPT
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.
Supporting Evidence:
PMID:22751931
A novel 4EHP-GIGYF2 translational repressor complex is essential for mammalian development.
GO:0031625 ubiquitin protein ligase binding
IPI
PMID:14623119
Human homologue of ariadne promotes the ubiquitylation of tr... 		ACCEPT
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.
Supporting Evidence:
PMID:14623119
Human homologue of ariadne promotes the ubiquitylation of translation initiation factor 4E homologous protein, 4EHP.
GO:0005515 protein binding
IPI
PMID:17368478
Structures of the human eIF4E homologous protein, h4EHP, in ... 		KEEP AS NON CORE
Summary: Generic protein-binding annotation from the structural/cap-binding study. The informative MF (cap binding) is captured separately.
Reason: Records interactions in the structural study; the generic term is not elevated.
Supporting Evidence:
PMID:17368478
Structures of the human eIF4E homologous protein, h4EHP, in its m7GTP-bound and unliganded forms.
GO:0000339 RNA cap binding
TAS
PMID:9582349
Cloning and characterization of 4EHP, a novel mammalian eIF4... 		ACCEPT
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.
Supporting Evidence:
PMID:9582349
Cloning and characterization of 4EHP, a novel mammalian eIF4E-related cap-binding protein.
GO:0008135 translation factor activity, RNA binding
TAS
PMID:9582349
Cloning and characterization of 4EHP, a novel mammalian eIF4... 		KEEP AS NON CORE
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.
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.
Supporting Evidence:
PMID:9582349
Cloning and characterization of 4EHP, a novel mammalian eIF4E-related cap-binding protein.

Core Functions

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:
RNA 7-methylguanosine cap binding
Cellular Locations:
cytosol P-body
Supporting Evidence:
  • PMID:17368478
    Structures of the human eIF4E homologous protein, h4EHP, in its m7GTP-bound and unliganded forms.

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:
RNA 7-methylguanosine cap binding
Directly Involved In:
negative regulation of translational initiation
Cellular Locations:
cytosol
Supporting Evidence:
  • PMID:32726578
    GIGYF2 and 4EHP Inhibit Translation Initiation of Defective Messenger RNAs to Assist Ribosome-Associated Quality Control.

References

GO_REF:0000002
Gene Ontology annotation through association of InterPro records with GO terms
GO_REF:0000033
Annotation inferences using phylogenetic trees
GO_REF:0000044
Gene Ontology annotation based on UniProtKB/Swiss-Prot Subcellular Location vocabulary mapping
GO_REF:0000052
Gene Ontology annotation based on curation of immunofluorescence data
GO_REF:0000120
Combined Automated Annotation using Multiple IEA Methods
PMID:14623119
Human homologue of ariadne promotes the ubiquitylation of translation initiation factor 4E homologous protein, 4EHP.
  • The RBR E3 ligase HHARI/ARIH1 interacts with 4EHP and promotes its polyubiquitylation.
PMID:15094042
Characterizing the interaction of the mammalian eIF4E-related protein 4EHP with 4E-BP1.
PMID:15161933
Comprehensive proteomic analysis of interphase and mitotic 14-3-3-binding proteins.
PMID:16189514
Towards a proteome-scale map of the human protein-protein interaction network.
PMID:17368478
Structures of the human eIF4E homologous protein, h4EHP, in its m7GTP-bound and unliganded forms.
  • 4EHP binds the m7G cap; crystal structures resolve 4EHP in m7GTP-bound and unliganded forms.
PMID:19060904
An empirical framework for binary interactome mapping.
PMID:22678294
An oxygen-regulated switch in the protein synthesis machinery.
PMID:22681889
The mRNA-bound proteome and its global occupancy profile on protein-coding transcripts.
PMID:22751931
A novel 4EHP-GIGYF2 translational repressor complex is essential for mammalian development.
  • Disruption of the m4EHP-GIGYF2 complex increases translation and causes perinatal lethality in mice, demonstrating 4EHP's repressor function.
PMID:23991149
Investigating the consequences of eIF4E2 (4EHP) interaction with 4E-transporter on its cellular distribution in HeLa cells.
  • 4EHP interacts with 4E-T (EIF4ENIF1), which influences its cytoplasmic and P-body distribution.
PMID:25416956
A proteome-scale map of the human interactome network.
PMID:25959826
Quantitative interaction proteomics of neurodegenerative disease proteins.
PMID:28487484
Cap-binding protein 4EHP effects translation silencing by microRNAs.
  • 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.
PMID:28514442
Architecture of the human interactome defines protein communities and disease networks.
PMID:31439631
Molecular basis for GIGYF-Me31B complex assembly in 4EHP-mediated translational repression.
  • 4EHP assembles with GIGYF and DDX6 into a translational-repressor complex; GIGYF binds 4EHP via a dedicated 4EHP-binding motif.
PMID:31515488
Extensive disruption of protein interactions by genetic variants across the allele frequency spectrum in human populations.
PMID:32726578
GIGYF2 and 4EHP Inhibit Translation Initiation of Defective Messenger RNAs to Assist Ribosome-Associated Quality Control.
  • 4EHP and GIGYF2 inhibit translation initiation on defective, ribosome-stalling mRNAs as a negative-feedback RQC mechanism.
PMID:32814053
Interactome Mapping Provides a Network of Neurodegenerative Disease Proteins and Uncovers Widespread Protein Aggregation in Affected Brains.
PMID:33053355
4EHP and GIGYF1/2 Mediate Translation-Coupled Messenger RNA Decay.
  • 4EHP-GIGYF1/2 complexes trigger co-translational mRNA decay of transcripts that experience ribosome pausing.
PMID:33961781
Dual proteome-scale networks reveal cell-specific remodeling of the human interactome.
PMID:35271311
OpenCell: Endogenous tagging for the cartography of human cellular organization.
PMID:35878012
SARS-CoV-2 impairs interferon production via NSP2-induced repression of mRNA translation.
  • SARS-CoV-2 nsp2 enhances GIGYF2-EIF4E2 association to repress IFNB1 translation, dampening the type I interferon response; 4EHP cap binding is required.
PMID:40205054
Multimodal cell maps as a foundation for structural and functional genomics.
PMID:9582349
Cloning and characterization of 4EHP, a novel mammalian eIF4E-related cap-binding protein.
  • 4EHP was cloned and characterized as a novel mammalian eIF4E-related cap- binding protein.
Reactome:R-HSA-1678842
Reactome pathway annotation (cytosol localization)
Reactome:R-HSA-1678843
Reactome pathway annotation (cytosol localization)
file:human/EIF4E2/EIF4E2-uniprot.txt
UniProt entry O60573 (IF4E2_HUMAN)
file:human/EIF4E2/EIF4E2-goa.tsv
GOA annotations for EIF4E2

Suggested Questions for Experts

Q: 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?

Q: 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

Experiment: 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.

Experiment: Quantitative proteomics of 4EHP complexes (GIGYF1/2, ZNF598, 4E-T, CCR4-NOT) across conditions to map context-dependent complex assembly and target mRNA selection.

📚 Additional Documentation

Notes

(EIF4E2-notes.md)

EIF4E2 / 4EHP (O60573) research notes

eIF4E homologous protein (4EHP). Class II eIF4E-family cap-binding protein.

Core function: non-canonical cap binding that REPRESSES initiation

4EHP binds the m7G cap but cannot recruit eIF4G, so it competes with eIF4E and blocks
eIF4F assembly, repressing cap-dependent translation initiation.

  • UniProt FUNCTION: "Recognizes and binds the 7-methylguanosine-containing mRNA cap during
    an early step in the initiation. Acts as a repressor of translation initiation ... In
    contrast to EIF4E, it is unable to bind eIF4G (EIF4G1, EIF4G2 or EIF4G3), suggesting that
    it acts by competing with EIF4E and block assembly of eIF4F at the cap"
  • Cap binding structurally confirmed PMID:17368478
  • Original cloning PMID:9582349

4EHP-GIGYF2 module + RQC

UniProt: "Component of the 4EHP-GYF2 complex ... In association with GIGYF2, assists
ribosome-associated quality control (RQC) by sequestering the mRNA cap, blocking ribosome
initiation and decreasing the translational load on problematic messages."
[PMID:32726578 RQC; PMID:22751931 development].

miRNA silencing via CCR4-NOT / P-body

PMID:28487484 Also controls IFNB1 via miR-34a negative feedback. P-body localization.

SARS-CoV-2

nsp2-GIGYF2 enhances GIGYF2-EIF4E2 binding to repress IFNB1 translation PMID:35878012.

Ubiquitylation by HHARI

PMID:14623119 -> GO:0031625 ubiquitin protein ligase
binding (HHARI/ARIH1). Real interaction.

IMPORTANT annotation caveats

  • IBA/IEA "translation initiation factor activity" (GO:0003743) and "part of eIF4F complex"
    (GO:0016281) and "translational initiation" (GO:0006413) are MISLEADING: 4EHP does NOT
    promote initiation and is NOT a functional eIF4F component (cannot bind eIF4G). It is a
    REPRESSOR. These are phylogenetic/electronic transfers from the eIF4E family and should be
    MARK_AS_OVER_ANNOTATED or MODIFY toward repressor terms.
  • A hypoxia-specific report (Uniacke) proposes 4EHP can support cap-dependent translation of
    specific mRNAs under hypoxia, but the dominant, well-established function is repression.
  • Many protein binding IPI = HT interactome -> KEEP_AS_NON_CORE / MARK_AS_OVER_ANNOTATED.
  • GO:1990261 pre-mRNA catabolic process (NAS ComplexPortal) -> MODIFY (mature mRNA decay).

Core MF/BP for review

  • MF: GO:0000340 RNA 7-methylguanosine cap binding (ACCEPT); GO:0045182 translation regulator /
    repressor; cap binding underlies repression.
  • BP: GO:0045947 negative regulation of translational initiation (ACCEPT, core);
    GO:0072344 rescue of stalled cytosolic ribosome (ACCEPT, RQC); GO:0035278 miRNA silencing.

Pn Notes

(EIF4E2-pn-notes.md)

EIF4E2 PN Consistency Notes

  • Generated: 2026-06-18
  • Project: PROTEOSTASIS
  • Scope: PN consistency rereview against local AIGR review and available deep-research artifacts
  • UniProt: O60573
  • AIGR review status: COMPLETE
  • Review batch: proteostasis-batch-2026-06-07c
  • Batch change status: added

Source Files Checked

Deep Research Files

  • No *-deep-research*.md file found in this gene directory.

AIGR Review Snapshot

  • 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/core annotation action counts: ACCEPT: 17; KEEP_AS_NON_CORE: 21; MARK_AS_OVER_ANNOTATED: 2; MODIFY: 3; REMOVE: 1

PN Consistency Summary

  • Consistency: Mostly consistent on biology but with a sharp, important divergence on one node. Deep research, notes, and review agree: 4EHP is a cap-binding REPRESSOR that cannot bind eIF4G and is NOT a productive eIF4F component; it acts in the 4EHP-GIGYF1/2 RQC/repression module. The review explicitly REMOVEs GO:0016281 (eukaryotic translation initiation factor 4F complex, IBA) and MARK_AS_OVER_ANNOTATED GO:0006413 (translational initiation) as misleading family-level transfers. The PN-node mapping for the "eIF4F complex" type, however, maps to exactly GO:0016281 and the initiation group to GO:0006413 — the two terms the review rejects/downgrades. Direct contradiction at the eIF4F-complex node.
  • PN story / NEW pressure: PN's RQC framing (GO:0006515, verified real) is fully borne out — review independently asserts negative regulation of translational initiation (GO:0045947, IDA) and rescue of stalled cytosolic ribosome (GO:0072344, IDA) for the RQC module. GO:0006515 is broader than these but defensible as an RQC umbrella; already captured (more specifically) by the review.
  • Evidence alignment: PN dossier lists no reference titles for EIF4E2; alignment is via projected terms. Review's RQC PMIDs (32726578, 35878012, 22751931, 33053355) cover the same repression/RQC biology the GO:0006515 node encodes. No PMID divergence; the only conflict is term-level (GO:0016281).
  • Verdict: Biology consistent; one node-level contradiction (PN GO:0016281 vs review REMOVE). RQC story already captured more precisely. Recommended edits: [MAP] flag the EIF4E2 "eIF4F complex" type→GO:0016281 projection as inappropriate (4EHP cannot bind eIF4G / is not an eIF4F component — see review REMOVE of GO:0016281); do not propagate GO:0016281 to O60573.

Full Consistency Review

  • UniProt: O60573 · batch: proteostasis-batch-2026-06-07c · review status: COMPLETE
  • PN placement: Translation|Cytosolic translation|Translation initiation|eIF4F complex AND Translation|Cytosolic translation|Ribosome-associated QC|other RQC processes ; PN-node mapping: initiation type=mapped→GO:0016281 (eIF4F complex); initiation group=mapped→GO:0006413; RQC group=mapped→GO:0006515; RQC type=no_mapping; class/branch context_only (GO:0002181/GO:0006412 too_broad).
  • Consistency: Mostly consistent on biology but with a sharp, important divergence on one node. Deep research, notes, and review agree: 4EHP is a cap-binding REPRESSOR that cannot bind eIF4G and is NOT a productive eIF4F component; it acts in the 4EHP-GIGYF1/2 RQC/repression module. The review explicitly REMOVEs GO:0016281 (eukaryotic translation initiation factor 4F complex, IBA) and MARK_AS_OVER_ANNOTATED GO:0006413 (translational initiation) as misleading family-level transfers. The PN-node mapping for the "eIF4F complex" type, however, maps to exactly GO:0016281 and the initiation group to GO:0006413 — the two terms the review rejects/downgrades. Direct contradiction at the eIF4F-complex node.
  • PN story / NEW pressure: PN's RQC framing (GO:0006515, verified real) is fully borne out — review independently asserts negative regulation of translational initiation (GO:0045947, IDA) and rescue of stalled cytosolic ribosome (GO:0072344, IDA) for the RQC module. GO:0006515 is broader than these but defensible as an RQC umbrella; already captured (more specifically) by the review.
  • Mapping strategy: The "eIF4F complex" type→GO:0016281 mapping is wrong for 4EHP and should be revisited at the PN level: 4EHP is a class-II eIF4E paralog that does not assemble into eIF4F. The PN node groups true eIF4F components, but projecting GO:0016281 onto EIF4E2 contradicts curated biology. RQC group→GO:0006515 is acceptable (broad umbrella over the review's GO:0045947/GO:0072344).
  • Evidence alignment: PN dossier lists no reference titles for EIF4E2; alignment is via projected terms. Review's RQC PMIDs (32726578, 35878012, 22751931, 33053355) cover the same repression/RQC biology the GO:0006515 node encodes. No PMID divergence; the only conflict is term-level (GO:0016281).
  • Verdict: Biology consistent; one node-level contradiction (PN GO:0016281 vs review REMOVE). RQC story already captured more precisely. Recommended edits: [MAP] flag the EIF4E2 "eIF4F complex" type→GO:0016281 projection as inappropriate (4EHP cannot bind eIF4G / is not an eIF4F component — see review REMOVE of GO:0016281); do not propagate GO:0016281 to O60573.

PN Dossier Context

  • review_batch: proteostasis-batch-2026-06-07c
  • review_yaml: genes/human/EIF4E2/EIF4E2-ai-review.yaml
  • PN workbook rows: 2

PN row 1: Translation | Cytosolic translation | Translation initiation | eIF4F complex

  • UniProt: O60573
  • In branches: TR
  • PN-node mapping records (path + ancestors):
    • [type] Translation|Cytosolic translation|Translation initiation|eIF4F complex
      status=mapped scope=ok_for_propagation_to_go GO=[GO:0016281 eukaryotic translation initiation factor 4F complex]
      rationale: This PN type denotes eIF4F complex components. The GO eukaryotic translation initiation factor 4F complex term resolves the previous deferred state.
    • [group] Translation|Cytosolic translation|Translation initiation
      status=mapped scope=ok_for_propagation_to_go GO=[GO:0006413 translational initiation]
      rationale: This PN group denotes cytosolic translation initiation factors and complexes. Translational initiation is the shared process target.
    • [class] Translation|Cytosolic translation
      status=context_only scope=too_broad_to_propagate GO=[GO:0002181 cytoplasmic translation]
      rationale: The PN class Cytosolic translation is centered on the cytoplasmic translation apparatus and process, but it also houses supporting machinery such as ribosome biogenesis factors. The GO process term is a useful high-level label for the class, but propagating it to all members would over-annotate genes whose PN placement is through assembly or maturation context rather than core cytoplasmic translation.
    • [branch] Translation
      status=context_only scope=too_broad_to_propagate GO=[GO:0006412 translation]
      rationale: The PN Translation branch is organized around the translation apparatus and immediately associated cotranslational quality-control systems. GO translation is the closest high-level process label, but the PN branch also contains adjacent machinery such as ribosome biogenesis and nascent-chain handling. Keeping this relationship is useful for interpretation, but it is too broad to project safely onto every member.

PN row 2: Translation | Cytosolic translation | Ribosome-associated QC | other RQC processes

  • UniProt: O60573
  • In branches: TR
  • PN-node mapping records (path + ancestors):
    • [type] Translation|Cytosolic translation|Ribosome-associated QC|other RQC processes
      status=no_mapping scope= GO=[]
      rationale: Reviewed as a broad PN category rather than a single GO class. The member genes span multiple activities, complexes, or contexts, so direct propagation from this node would overstate the shared biology.
    • [group] Translation|Cytosolic translation|Ribosome-associated QC
      status=mapped scope=ok_for_propagation_to_go GO=[GO:0006515 protein quality control for misfolded or incompletely synthesized proteins]
      rationale: The PN ribosome-associated quality-control group covers surveillance and disposal of stalled or defective nascent-chain translation products. GO lacks a dedicated ribosome-associated QC term in the local cache, so the broader protein-quality-control process is the best supported target.
    • [class] Translation|Cytosolic translation
      status=context_only scope=too_broad_to_propagate GO=[GO:0002181 cytoplasmic translation]
      rationale: The PN class Cytosolic translation is centered on the cytoplasmic translation apparatus and process, but it also houses supporting machinery such as ribosome biogenesis factors. The GO process term is a useful high-level label for the class, but propagating it to all members would over-annotate genes whose PN placement is through assembly or maturation context rather than core cytoplasmic translation.
    • [branch] Translation
      status=context_only scope=too_broad_to_propagate GO=[GO:0006412 translation]
      rationale: The PN Translation branch is organized around the translation apparatus and immediately associated cotranslational quality-control systems. GO translation is the closest high-level process label, but the PN branch also contains adjacent machinery such as ribosome biogenesis and nascent-chain handling. Keeping this relationship is useful for interpretation, but it is too broad to project safely onto every member.

Projected GO annotations (3)

  • GO:0006413 translational initiation | scope=ok_for_propagation_to_go | goa_status=already_in_goa_exact | from=Translation|Cytosolic translation|Translation initiation
  • GO:0016281 eukaryotic translation initiation factor 4F complex | scope=ok_for_propagation_to_go | goa_status=already_in_goa_exact | from=Translation|Cytosolic translation|Translation initiation|eIF4F complex
  • GO:0006515 protein quality control for misfolded or incompletely synthesized proteins | scope=ok_for_propagation_to_go | goa_status=new_to_goa | from=Translation|Cytosolic translation|Ribosome-associated QC

Note

This file is generated from the current PROTEOSTASIS phase-1 dossier and local gene-review artifacts. Edit the source review, PN mapping, or dossier rather than this generated note when correcting the underlying curation.

📄 View Raw YAML

 
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: []