GIGYF2

UniProt ID: Q6Y7W6
Organism: Homo sapiens
Review Status: COMPLETE
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Gene Description

GIGYF2 (GRB10-interacting GYF protein 2; TNRC15) is the principal scaffold of the 4EHP-GYF2 translational-repressor complex. Through an N-terminal 4EHP-binding motif it binds the non-canonical cap-binding protein 4EHP (EIF4E2), which occupies the mRNA 5' cap but cannot recruit eIF4G, thereby blocking cap-dependent translation initiation. Its central GYF domain bridges EIF4E2 to RNA-associated repressors, including the AU-rich-element protein ZFP36/tristetraprolin, the miRNA-pathway Argonaute AGO2/TNRC6 machinery, and the collided-ribosome sensor E3 ligase ZNF598, and it recruits the DEAD-box helicase/decapping effector DDX6, coupling translational repression to mRNA destabilization and decay. A major role is in ribosome-associated quality control: on mRNAs that cause ribosome stalling, GIGYF2-EIF4E2 impose a negative-feedback loop that suppresses further initiation, reducing translational load and working in parallel with degradation of the stalled nascent chain. The 4EHP-GIGYF2 complex is essential for mammalian embryonic development, and compromised GIGYF2 function causes neurodevelopmental and neuropsychiatric phenotypes; the gene lies at the PARK11 locus (Parkinson disease 11), although its causal role in Parkinson disease is unclear. GIGYF2 is predominantly cytosolic and also localizes to stress granules, P-bodies and neuronal perikarya/proximal dendrites; SARS-CoV-2 nsp2 co-opts GIGYF2 to repress interferon (IFNB1) translation. A separate legacy role, via the GRB10 adapter, modulates IGF-1/insulin receptor signaling.

Existing Annotations Review

GO Term Evidence Action Reason
GO:0000900 mRNA regulatory element binding translation repressor activity
IBA
GO_REF:0000033 		ACCEPT
Summary: Captures GIGYF2's role as a sequence-/element-directed translational repressor: it is recruited by RNA-binding adaptors (ZFP36/TTP, TNRC6/AGO2) to specific mRNA elements and represses their translation via 4EHP. Well supported and core.
Reason: GIGYF2 bridges EIF4E2 to element-binding proteins (e.g. ZFP36/TTP on AU-rich elements) to repress translation of specific transcripts, consistent with this MF.
Supporting Evidence:
file:human/GIGYF2/GIGYF2-uniprot.txt
acts as a factor that bridges EIF4E2 to ZFP36/TTP, linking
PMID:27157137
upon tethering to a reporter mRNA, GIGYF2 exhibits strong, dose-dependent silencing activity, involving both mRNA destabilization and translational repression.
GO:0045947 negative regulation of translational initiation
IBA
GO_REF:0000033 		ACCEPT
Summary: Core function: the 4EHP-GIGYF2 complex represses cap-dependent translation initiation. Strongly supported phylogenetically and experimentally.
Reason: UniProt and primary literature establish the 4EHP-GYF2 complex as a repressor of translation initiation.
Supporting Evidence:
file:human/GIGYF2/GIGYF2-uniprot.txt
Key component of the 4EHP-GYF2 complex, a multiprotein
GO:0016020 membrane
IBA
GO_REF:0000033 		MARK AS OVER ANNOTATED
Summary: Broad 'membrane' localization, phylogenetically inferred. GIGYF2 is a cytosolic mRNA-associated protein; any membrane association is peripheral (e.g. with membrane-associated translation sites or vesicles) and not its site of action.
Reason: GIGYF2 has no membrane-spanning domain; the informative localizations are cytosol, stress granules and P-bodies. The generic 'membrane' is_active_in is not supported as a functional site.
Supporting Evidence:
file:human/GIGYF2/GIGYF2-uniprot.txt
Key component of the 4EHP-GYF2 complex, a multiprotein
GO:0005829 cytosol
IBA
GO_REF:0000033 		ACCEPT
Summary: GIGYF2 acts in the cytosol on translating mRNAs. Well supported and consistent with IDA evidence.
Reason: Cytosolic activity is expected for a translational-repression/mRNA-decay adaptor and is supported by direct localization data.
Supporting Evidence:
file:human/GIGYF2/GIGYF2-uniprot.txt
assists ribosome-associated
GO:0031982 vesicle
IBA
GO_REF:0000033 		KEEP AS NON CORE
Summary: Vesicle localization, phylogenetically inferred. GIGYF2 is found in endosomal compartments in brain, but vesicle is not its primary functional site.
Reason: GIGYF2 was reported in endosomal compartments in brain (PMID:20670374); a vesicle/endosome association is plausible but peripheral to its translational repression role.
Supporting Evidence:
PMID:20670374
GIGYF2 is present in endosomal compartments in the mammalian brains and enhances IGF-1-induced ERK1/2 activation.
GO:0043204 perikaryon
IBA
GO_REF:0000033 		KEEP AS NON CORE
Summary: Neuronal perikaryon localization, phylogenetically inferred and supported by IDA in brain. Relevant to GIGYF2's neuronal roles.
Reason: GIGYF2 localizes to neuronal perikarya and proximal dendrites (PMID:20670374); a cell-type-specific localization rather than a core molecular site.
Supporting Evidence:
PMID:20670374
localised in neuronal perikarya and proximal dendrites.
GO:0048009 insulin-like growth factor receptor signaling pathway
IBA
GO_REF:0000033 		KEEP AS NON CORE
Summary: Legacy GRB10-linked role modulating IGF-1 receptor signaling. Real but secondary to the translational-repression/RQC function.
Reason: GIGYF2 enhances IGF-1-induced ERK signaling via GRB10, but the dominant, broadly conserved function is translational repression in the 4EHP-GYF2 complex.
Supporting Evidence:
PMID:20670374
enhances IGF-1-induced ERK1/2 activation.
GO:1990635 proximal dendrite
IBA
GO_REF:0000033 		KEEP AS NON CORE
Summary: Proximal dendrite localization, supported by IDA in neurons. Relevant to local translational control in dendrites.
Reason: GIGYF2 localizes to proximal dendrites of neurons (PMID:20670374), consistent with a role in local translational repression; a cell-type-specific site.
Supporting Evidence:
PMID:20670374
localised in neuronal perikarya and proximal dendrites.
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. Records an interaction but the term is uninformative; informative interactions (EIF4E2, DDX6) are captured elsewhere.
Reason: 'protein binding' does not convey GIGYF2's molecular function.
Supporting Evidence:
file:human/GIGYF2/GIGYF2-goa.tsv
PMID:15161933
GO:0005515 protein binding
IPI
PMID:28698298
GIGYF1/2 proteins use auxiliary sequences to selectively bin... 		KEEP AS NON CORE
Summary: Generic IPI protein-binding annotation from a ubiquitin-signaling interaction dataset. Uninformative as a molecular function.
Reason: Records a real interaction but the generic term is not elevated to core.
Supporting Evidence:
file:human/GIGYF2/GIGYF2-goa.tsv
PMID:28698298
GO:0005515 protein binding
IPI
PMID:35271311
OpenCell: Endogenous tagging for the cartography of human ce... 		KEEP AS NON CORE
Summary: Generic IPI protein-binding annotation. Uninformative as a molecular function.
Reason: Records a real interaction but the generic term provides no functional insight.
Supporting Evidence:
file:human/GIGYF2/GIGYF2-goa.tsv
PMID:35271311
GO:0005737 cytoplasm
IEA
GO_REF:0000107 		ACCEPT
Summary: Cytoplasmic localization (IEA). Consistent with the well-established cytosolic activity of GIGYF2.
Reason: GIGYF2 is a cytoplasmic mRNA-associated protein; cytoplasm localization is well supported.
Supporting Evidence:
file:human/GIGYF2/GIGYF2-uniprot.txt
assists ribosome-associated
GO:0016020 membrane
IEA
GO_REF:0000107 		MARK AS OVER ANNOTATED
Summary: Generic 'membrane' localization (IEA). GIGYF2 is not an integral membrane protein.
Reason: No transmembrane domain; the informative localizations are cytosol, stress granules and P-bodies.
Supporting Evidence:
file:human/GIGYF2/GIGYF2-uniprot.txt
Key component of the 4EHP-GYF2 complex, a multiprotein
GO:0031982 vesicle
IEA
GO_REF:0000107 		KEEP AS NON CORE
Summary: Vesicle localization (IEA), corroborated by endosomal localization in brain.
Reason: Peripheral vesicle/endosome association reported in neurons; not the core site.
Supporting Evidence:
PMID:20670374
GIGYF2 is present in endosomal compartments in the mammalian brains and enhances IGF-1-induced ERK1/2 activation.
GO:0043204 perikaryon
IEA
GO_REF:0000107 		KEEP AS NON CORE
Summary: Perikaryon localization (IEA), corroborated by IDA in neurons.
Reason: Cell-type-specific neuronal localization, supported experimentally.
Supporting Evidence:
PMID:20670374
localised in neuronal perikarya and proximal dendrites.
GO:1990635 proximal dendrite
IEA
GO_REF:0000107 		KEEP AS NON CORE
Summary: Proximal dendrite localization (IEA), corroborated by IDA in neurons.
Reason: Cell-type-specific neuronal localization, supported experimentally.
Supporting Evidence:
PMID:20670374
localised in neuronal perikarya and proximal dendrites.
GO:0005829 cytosol
IDA
GO_REF:0000052 		ACCEPT
Summary: Direct (immunofluorescence) cytosol localization. Consistent with GIGYF2's cytosolic activity.
Reason: Cytosolic localization is experimentally supported and matches its function.
Supporting Evidence:
file:human/GIGYF2/GIGYF2-uniprot.txt
assists ribosome-associated
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-GIGYF2 co-translational mRNA-decay complex. The biology (decay of translated, ribosome-stalled mRNAs) 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; a mature-mRNA catabolic term better reflects the evidence.
Supporting Evidence:
PMID:33053355
4EHP and GIGYF1/2 Mediate Translation-Coupled Messenger RNA Decay.
GO:0045947 negative regulation of translational initiation
IDA
PMID:32726578
GIGYF2 and 4EHP Inhibit Translation Initiation of Defective ... 		ACCEPT
Summary: Direct evidence that GIGYF2 (with 4EHP) inhibits translation initiation on ribosome-stalling mRNAs as a negative-feedback RQC mechanism. Core function.
Reason: CRISPR screening and reporter assays show GIGYF2/4EHP specifically inhibit initiation on defective messages.
Supporting Evidence:
PMID:32726578
This negative feedback loop is mediated by two translation inhibitors, GIGYF2 and 4EHP.
GO:0045947 negative regulation of translational initiation
IDA
PMID:35878012
SARS-CoV-2 impairs interferon production via NSP2-induced re... 		ACCEPT
Summary: Direct evidence that GIGYF2/4EHP repress translation initiation of IFNB1 mRNA, co-opted by SARS-CoV-2 nsp2. Supports the core repressor function.
Reason: GIGYF2/4EHP repress Ifnb1 translation; nsp2 enhances GIGYF2-EIF4E2 binding to increase this repression.
Supporting Evidence:
PMID:35878012
Here, we document a mechanism by which the NSP2 protein impedes IFN-Ξ² expression through translational repression of Ifnb1 mRNA by coopting the GIGYF2/4EHP complex
GO:0060090 molecular adaptor activity
IDA
PMID:32726578
GIGYF2 and 4EHP Inhibit Translation Initiation of Defective ... 		ACCEPT
Summary: GIGYF2 functions as a molecular adaptor that bridges EIF4E2 to RNA-associated factors and ZNF598/RQC machinery. Core molecular function.
Reason: GIGYF2 bridges EIF4E2 to ZFP36/TTP, DDX6 and the RQC apparatus; an adaptor MF is appropriate and informative.
Supporting Evidence:
file:human/GIGYF2/GIGYF2-uniprot.txt
acts as a factor that bridges EIF4E2 to ZFP36/TTP, linking
GO:0060090 molecular adaptor activity
IDA
PMID:35878012
SARS-CoV-2 impairs interferon production via NSP2-induced re... 		ACCEPT
Summary: GIGYF2 adaptor activity bridging EIF4E2 and nsp2/RNA factors to repress IFNB1. Supports the adaptor MF.
Reason: nsp2 co-opts the GIGYF2 adaptor to recruit 4EHP to IFNB1 mRNA, consistent with a bridging/adaptor function.
Supporting Evidence:
PMID:35878012
Here, we document a mechanism by which the NSP2 protein impedes IFN-Ξ² expression through translational repression of Ifnb1 mRNA by coopting the GIGYF2/4EHP complex
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: GIGYF2/4EHP repress IFNB1 (type I IFN) translation; this is the basis of nsp2's immune evasion. A genuine, though context-specific, role.
Reason: The IFN-repression role is a specific consequence of GIGYF2's general translational repression activity acting on IFNB1 mRNA, exploited during SARS-CoV-2 infection; relevant but not the core, ubiquitous function.
Supporting Evidence:
PMID:35878012
Here, we document a mechanism by which the NSP2 protein impedes IFN-Ξ² expression through translational repression of Ifnb1 mRNA by coopting the GIGYF2/4EHP complex
GO:0072344 rescue of stalled cytosolic ribosome
IDA
PMID:32726578
GIGYF2 and 4EHP Inhibit Translation Initiation of Defective ... 		ACCEPT
Summary: GIGYF2/4EHP participate in ribosome-associated quality control by suppressing new initiation on mRNAs that stall ribosomes, working in concert with RQC degradation pathways. Core RQC function.
Reason: Direct evidence places GIGYF2/4EHP in the RQC response to stalled ribosomes, acting in parallel with degradation of the stalled nascent chain.
Supporting Evidence:
PMID:32726578
GIGYF2 and 4EHP Inhibit Translation Initiation of Defective Messenger RNAs to Assist Ribosome-Associated Quality Control.
file:human/GIGYF2/GIGYF2-uniprot.txt
assists ribosome-associated quality control
GO:0005515 protein binding
IPI
PMID:31439631
Molecular basis for GIGYF-Me31B complex assembly in 4EHP-med... 		MODIFY
Summary: IPI annotation capturing the structurally defined direct interactions of GIGYF2 with EIF4E2, ZFP36/TTP and DDX6. Functionally central but 'protein binding' is too generic.
Reason: The interactions defined here (EIF4E2 via 4EHP-binding motif; DDX6 via a dedicated motif; TTP via P-P-P-P-G repeats) underlie translational repression; a specific eIF4E-binding / repression MF is more informative than generic protein binding.
Supporting Evidence:
file:human/GIGYF2/GIGYF2-uniprot.txt
Interacts (via the 4EHP-binding motif) with EIF4E2;
GO:0045296 cadherin binding
HDA
PMID:25468996
E-cadherin interactome complexity and robustness resolved by... 		MARK AS OVER ANNOTATED
Summary: 'cadherin binding' from a high-throughput proximity/affinity proteomics dataset. There is no functional evidence that cadherin binding is part of GIGYF2 biology.
Reason: This term commonly arises as an artifact of HT BioID/AP-MS proximity datasets and does not reflect a characterized GIGYF2 function.
Supporting Evidence:
file:human/GIGYF2/GIGYF2-goa.tsv
PMID:25468996
GO:0005515 protein binding
IPI
PMID:20878056
Critical involvement of RQCD1 in the EGFR-Akt pathway in mam... 		KEEP AS NON CORE
Summary: Generic protein-binding annotation from an EGFR-Akt/RQCD1 study. Uninformative as a molecular function.
Reason: Records interactions in a signaling-network context but the generic term is not elevated.
Supporting Evidence:
PMID:20878056
Critical involvement of RQCD1 in the EGFR-Akt pathway in mammary carcinogenesis.
GO:0032991 protein-containing complex
IDA
PMID:20878056
Critical involvement of RQCD1 in the EGFR-Akt pathway in mam... 		KEEP AS NON CORE
Summary: Generic complex membership. GIGYF2 is a bona fide complex component (4EHP-GYF2), but the top-level term is uninformative.
Reason: The specific complex (4EHP-GIGYF2-DDX6/ZNF598) is captured by the functional annotations; 'protein-containing complex' conveys no specific information.
Supporting Evidence:
PMID:20878056
Critical involvement of RQCD1 in the EGFR-Akt pathway in mammary carcinogenesis.
GO:0005515 protein binding
IPI
PMID:20670374
GIGYF2 is present in endosomal compartments in the mammalian... 		KEEP AS NON CORE
Summary: Generic protein-binding annotation from the brain IGF/endosome study. Uninformative as a molecular function.
Reason: Records a real interaction but the generic term is not elevated.
Supporting Evidence:
PMID:20670374
GIGYF2 is present in endosomal compartments in the mammalian brains and enhances IGF-1-induced ERK1/2 activation.
GO:0005515 protein binding
IPI
PMID:20696395
Conserved beta-hairpin recognition by the GYF domains of Smy... 		KEEP AS NON CORE
Summary: Generic protein-binding annotation from the GYF-domain proline-rich-sequence recognition study. The specific MF (proline-rich region binding) is captured separately.
Reason: Records the GYF-domain PRS interaction; the informative MF is GO:0070064.
Supporting Evidence:
PMID:20696395
Conserved beta-hairpin recognition by the GYF domains of Smy2 and GIGYF2 in mRNA surveillance and vesicular transport complexes.
GO:0005515 protein binding
IPI
PMID:27157137
Post-transcriptional gene silencing activity of human GIGYF2... 		KEEP AS NON CORE
Summary: Generic protein-binding annotation from the AGO2/miRNA silencing study. The functional outcome (silencing/destabilization) is captured by other terms.
Reason: Records the GIGYF2-AGO2 interaction; the generic term is not elevated.
Supporting Evidence:
PMID:27157137
upon tethering to a reporter mRNA, GIGYF2 exhibits strong, dose-dependent silencing activity, involving both mRNA destabilization and translational repression.
GO:0005768 endosome
IDA
PMID:20670374
GIGYF2 is present in endosomal compartments in the mammalian... 		KEEP AS NON CORE
Summary: Endosome localization in brain (IDA). A genuine but peripheral localization.
Reason: GIGYF2 was found in endosomal compartments in brain; relevant to its neuronal/IGF role but not its core translational-repression site.
Supporting Evidence:
PMID:20670374
GIGYF2 is present in endosomal compartments in the mammalian brains and enhances IGF-1-induced ERK1/2 activation.
GO:0005783 endoplasmic reticulum
IDA
PMID:20696395
Conserved beta-hairpin recognition by the GYF domains of Smy... 		KEEP AS NON CORE
Summary: ER localization reported alongside GYF-domain studies. GIGYF2 is mainly cytosolic; ER association is likely peripheral (e.g. at ER-bound translation sites).
Reason: Peripheral ER association is plausible for a translation-associated factor but is not its defining site.
Supporting Evidence:
PMID:20696395
Conserved beta-hairpin recognition by the GYF domains of Smy2 and GIGYF2 in mRNA surveillance and vesicular transport complexes.
GO:0005794 Golgi apparatus
IDA
PMID:20696395
Conserved beta-hairpin recognition by the GYF domains of Smy... 		KEEP AS NON CORE
Summary: Golgi localization reported alongside GYF-domain studies. GIGYF2 is mainly cytosolic; Golgi association is peripheral.
Reason: Not the defining functional site; a peripheral localization.
Supporting Evidence:
PMID:20696395
Conserved beta-hairpin recognition by the GYF domains of Smy2 and GIGYF2 in mRNA surveillance and vesicular transport complexes.
GO:0010494 cytoplasmic stress granule
IDA
PMID:20696395
Conserved beta-hairpin recognition by the GYF domains of Smy... 		ACCEPT
Summary: Stress granule localization (IDA). Consistent with GIGYF2's role in translational repression and mRNA storage/decay.
Reason: GIGYF2 partitions into stress granules, consistent with its repressed-mRNP associations.
Supporting Evidence:
PMID:20696395
Conserved beta-hairpin recognition by the GYF domains of Smy2 and GIGYF2 in mRNA surveillance and vesicular transport complexes.
GO:0016441 post-transcriptional gene silencing
IDA
PMID:27157137
Post-transcriptional gene silencing activity of human GIGYF2... 		ACCEPT
Summary: GIGYF2 is a silencing effector in the miRNA/AGO2 pathway, repressing translation and destabilizing target mRNAs when tethered.
Reason: Tethering assays show strong, dose-dependent silencing by GIGYF2 via the AGO2/miRNA pathway.
Supporting Evidence:
PMID:27157137
upon tethering to a reporter mRNA, GIGYF2 exhibits strong, dose-dependent silencing activity, involving both mRNA destabilization and translational repression.
GO:0043204 perikaryon
IDA
PMID:20670374
GIGYF2 is present in endosomal compartments in the mammalian... 		KEEP AS NON CORE
Summary: Direct neuronal perikaryon localization. Relevant to neuronal function.
Reason: Cell-type-specific neuronal localization supported by direct evidence.
Supporting Evidence:
PMID:20670374
localised in neuronal perikarya and proximal dendrites.
GO:0048009 insulin-like growth factor receptor signaling pathway
IMP
PMID:20670374
GIGYF2 is present in endosomal compartments in the mammalian... 		KEEP AS NON CORE
Summary: IMP evidence that GIGYF2 modulates IGF-1 receptor/ERK signaling. Legacy GRB10-linked role; secondary to translational repression.
Reason: GIGYF2 enhances IGF-1-induced ERK activation, but its dominant conserved function is translational repression.
Supporting Evidence:
PMID:20670374
enhances IGF-1-induced ERK1/2 activation.
GO:0061157 mRNA destabilization
IDA
PMID:27157137
Post-transcriptional gene silencing activity of human GIGYF2... 		ACCEPT
Summary: GIGYF2 destabilizes target mRNAs (in addition to repressing their translation), consistent with coupling repression to decay via DDX6/decapping.
Reason: Tethered GIGYF2 causes mRNA destabilization; this is a genuine functional output.
Supporting Evidence:
PMID:27157137
upon tethering to a reporter mRNA, GIGYF2 exhibits strong, dose-dependent silencing activity, involving both mRNA destabilization and translational repression.
GO:0070064 proline-rich region binding
IDA
PMID:20696395
Conserved beta-hairpin recognition by the GYF domains of Smy... 		ACCEPT
Summary: The GYF domain of GIGYF2 recognizes proline-rich sequences in partner proteins, mediating recruitment to mRNA-surveillance/transport complexes. Informative MF.
Reason: Direct structural evidence that the GIGYF2 GYF domain binds proline-rich sequences (PRS), the basis of its adaptor interactions.
Supporting Evidence:
PMID:20696395
Conserved beta-hairpin recognition by the GYF domains of Smy2 and GIGYF2 in mRNA surveillance and vesicular transport complexes.
GO:1990635 proximal dendrite
IDA
PMID:20670374
GIGYF2 is present in endosomal compartments in the mammalian... 		KEEP AS NON CORE
Summary: Direct proximal-dendrite localization in neurons.
Reason: Cell-type-specific neuronal localization supported by direct evidence; consistent with local translational control.
Supporting Evidence:
PMID:20670374
localised in neuronal perikarya and proximal dendrites.
GO:0016020 membrane
HDA
PMID:19946888
Defining the membrane proteome of NK cells. 		MARK AS OVER ANNOTATED
Summary: 'membrane' from a high-throughput proteomics dataset. GIGYF2 is not an integral membrane protein.
Reason: No transmembrane domain; HT membrane-fraction co-purification does not establish a functional membrane localization.
Supporting Evidence:
file:human/GIGYF2/GIGYF2-goa.tsv
PMID:19946888
GO:0003723 RNA binding
HDA
PMID:22681889
The mRNA-bound proteome and its global occupancy profile on ... 		ACCEPT
Summary: RNA binding from a proteome-wide mRNA-interactome capture study. Consistent with GIGYF2's association with target mRNAs and ribosomes.
Reason: GIGYF2 was identified as an mRNA-bound protein, consistent with its co-translational binding to target transcripts.
Supporting Evidence:
file:human/GIGYF2/GIGYF2-goa.tsv
PMID:22681889
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; its disruption increases translation and causes perinatal lethality in mice. Core.
Reason: Disruption of the m4EHP-GIGYF2 complex leads to increased translation, directly demonstrating GIGYF2's negative regulation of translation.
Supporting Evidence:
PMID:22751931
Disruption of the m4EHP-GIGYF2 complex leads to increased translation and perinatal lethality in mice.

Core Functions

GIGYF2 binds the non-canonical cap-binding protein 4EHP/EIF4E2 via its N-terminal 4EHP-binding motif, the molecular basis for cap sequestration and repression of cap-dependent translation initiation.

Molecular Function:
eukaryotic initiation factor 4E binding
Cellular Locations:
cytosol
Supporting Evidence:
  • file:human/GIGYF2/GIGYF2-uniprot.txt
    Interacts (via the 4EHP-binding motif) with EIF4E2;

GIGYF2 acts as a molecular adaptor that bridges EIF4E2 to RNA-associated repressors (ZFP36/TTP, AGO2/TNRC6), the decapping helicase DDX6, and the collided-ribosome sensor ZNF598, organizing the 4EHP-GYF2 repression/decay module.

Molecular Function:
molecular adaptor activity
Cellular Locations:
cytosol
Supporting Evidence:
  • file:human/GIGYF2/GIGYF2-uniprot.txt
    acts as a factor that bridges EIF4E2 to ZFP36/TTP, linking

As an element-directed translational repressor, GIGYF2 represses initiation of specific mRNAs and, on ribosome-stalling messages, imposes a negative-feedback loop that suppresses further initiation as part of ribosome-associated quality control.

Molecular Function:
mRNA regulatory element binding translation repressor activity
Cellular Locations:
cytosol cytoplasmic stress granule
Supporting Evidence:
  • PMID:32726578
    This negative feedback loop is mediated by two translation inhibitors, GIGYF2 and 4EHP.

References

GO_REF:0000033
Annotation inferences using phylogenetic trees
GO_REF:0000052
Gene Ontology annotation based on curation of immunofluorescence data
GO_REF:0000107
Automatic transfer of experimentally verified manual GO annotation data to orthologs using Ensembl Compara
PMID:15161933
Comprehensive proteomic analysis of interphase and mitotic 14-3-3-binding proteins.
PMID:19946888
Defining the membrane proteome of NK cells.
PMID:20670374
GIGYF2 is present in endosomal compartments in the mammalian brains and enhances IGF-1-induced ERK1/2 activation.
  • GIGYF2 localizes to endosomal compartments, neuronal perikarya and proximal dendrites, and enhances IGF-1-induced ERK1/2 activation; mutant GIGYF2 did not localize to Lewy bodies.
PMID:20696395
Conserved beta-hairpin recognition by the GYF domains of Smy2 and GIGYF2 in mRNA surveillance and vesicular transport complexes.
  • The GYF domain of GIGYF2 recognizes proline-rich sequences via a conserved beta-hairpin, mediating its assembly into mRNA-surveillance and vesicular-transport complexes.
PMID:20878056
Critical involvement of RQCD1 in the EGFR-Akt pathway in mammary carcinogenesis.
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.
  • GIGYF2 directly interacts with m4EHP; this interaction stabilizes both proteins, and disruption of the m4EHP-GIGYF2 complex increases translation and causes perinatal lethality in mice.
PMID:25468996
E-cadherin interactome complexity and robustness resolved by quantitative proteomics.
PMID:27157137
Post-transcriptional gene silencing activity of human GIGYF2.
  • Full-length GIGYF2 coimmunoprecipitates with AGO2 and, when tethered to a reporter mRNA, exhibits strong dose-dependent silencing involving both mRNA destabilization and translational repression.
PMID:28698298
GIGYF1/2 proteins use auxiliary sequences to selectively bind to 4EHP and repress target mRNA expression.
PMID:31439631
Molecular basis for GIGYF-Me31B complex assembly in 4EHP-mediated translational repression.
  • GIGYF2 interacts directly with EIF4E2 (via the 4EHP-binding motif), with ZFP36/TTP (via P-P-P-P-G repeats), and with DDX6 (via a dedicated motif binding the DDX6 RecA2 domain).
PMID:32726578
GIGYF2 and 4EHP Inhibit Translation Initiation of Defective Messenger RNAs to Assist Ribosome-Associated Quality Control.
  • Failed translation triggers GIGYF2/4EHP-mediated inhibition of translation initiation on that message, a negative-feedback RQC mechanism acting in concert with degradation of the stalled nascent polypeptide.
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: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 binds GIGYF2 and enhances GIGYF2-EIF4E2 association to repress translation of IFNB1 mRNA, dampening the type I interferon response.
file:human/GIGYF2/GIGYF2-uniprot.txt
UniProt entry Q6Y7W6 (GGYF2_HUMAN)
file:human/GIGYF2/GIGYF2-goa.tsv
GOA annotations for GIGYF2

Suggested Questions for Experts

Q: Which endogenous mRNAs depend on GIGYF2 (versus GIGYF1) for RQC-coupled repression, and how is target selection partitioned between ZNF598-, TTP- and miRNA-directed recruitment?

Q: How do GIGYF2 loss-of-function variants produce neurodevelopmental/neuropsychiatric phenotypes - via failure of RQC-coupled repression, dysregulated dendritic translation, or altered IGF signaling?

Suggested Experiments

Experiment: Ribosome profiling plus mRNA stability measurements in GIGYF2 knockout cells (and 4EHP-binding-motif or GYF-domain separation-of-function mutants) to define target mRNAs and the contribution of each interaction.

Experiment: Reconstitution of the 4EHP-GIGYF2-ZNF598 module on stalled-ribosome substrates to test whether GIGYF2 directly couples collision sensing to initiation shutdown.

πŸ“š Additional Documentation

Notes

(GIGYF2-notes.md)

GIGYF2 (Q6Y7W6) research notes

GRB10-interacting GYF protein 2 (TNRC15, PARK11). Paralog of GIGYF1. GIGYF family.

Core function: 4EHP-GIGYF2 translational repressor / RQC

GIGYF2 is the key scaffold of the 4EHP-GYF2 complex (EIF4E2 + GIGYF2 + ZNF598), a
translation-initiation repressor that also couples repression to mRNA decay.

  • UniProt FUNCTION: "Key component of the 4EHP-GYF2 complex, a multiprotein complex
    that acts as a repressor of translation initiation ... acts as a factor that bridges
    EIF4E2 to ZFP36/TTP, linking translation repression with mRNA decay ... Also recruits
    and bridges the association of the 4EHP complex with the decapping effector protein DDX6"
  • RQC role PMID:32726578 and ["In association with EIF4E2, assists ribosome-associated
    quality control (RQC) by sequestering the mRNA cap, blocking ribosome initiation and
    decreasing the translational load on problematic messages." (UniProt)]. GIGYF2/EIF4E2 work
    downstream and independently of ZNF598.
  • 4EHP-GIGYF2 essential for mammalian development; direct EIF4E2 interaction required to
    stabilize both proteins PMID:22751931

miRNA silencing / mRNA destabilization

GIGYF2 binds AGO2 (via GYF domain) and acts as a silencing effector: PMID:27157137

SARS-CoV-2 nsp2 / interferon repression

nsp2 binds GIGYF2 and enhances GIGYF2-EIF4E2 binding to repress IFNB1 translation:
PMID:35878012 -> GO:0060339 negative reg type I IFN, GO:0060090 molecular adaptor activity.

IGF/GRB10 + neuronal localization

PMID:20670374 Localized in neuronal perikarya and proximal
dendrites; did not localize to Lewy bodies. Basis of perikaryon/proximal dendrite/endosome
and IGF signaling annotations.

GYF domain / proline-rich binding

PMID:20696395 GYF domains recognize proline-rich
sequences -> GO:0070064 proline-rich region binding. Also reports SG/ER/Golgi localization.

Disease

PARK11 / Parkinson disease 11 susceptibility β€” UniProt notes association is "however unclear"
and "GIGYF2 does not play a major role in Parkinson disease etiology". Also neurodevelopmental/
neuropsychiatric phenotypes with compromised GIGYF2 (PMID:32726578).

Annotation plan (highlights)

  • Core MF: GO:0000900 mRNA regulatory element binding translation repressor activity (ACCEPT);
    GO:0060090 molecular adaptor activity (ACCEPT, bridges EIF4E2-TTP/DDX6); GO:0008190 eIF4E
    binding could be added as NEW.
  • Core BP: GO:0045947 neg reg translational initiation (ACCEPT); GO:0072344 rescue of stalled
    cytosolic ribosome (ACCEPT, RQC); GO:0017148 neg reg translation (ACCEPT); GO:0061157 mRNA
    destabilization, GO:0016441 post-transcriptional gene silencing (ACCEPT non-core/ACCEPT).
  • protein binding IPI x many -> KEEP_AS_NON_CORE / MARK_AS_OVER_ANNOTATED (HT interactome).
  • GO:0045296 cadherin binding (HDA, BioID proximity) -> MARK_AS_OVER_ANNOTATED (proximity artifact).
  • GO:1990261 pre-mRNA catabolic process (NAS ComplexPortal) -> MODIFY (mature mRNA decay).
  • Localizations (cytosol, SG, endosome, ER, Golgi, membrane, perikaryon, dendrite, vesicle):
    cytosol/SG/perikaryon/dendrite/endosome ACCEPT; membrane/vesicle/ER/Golgi KEEP_AS_NON_CORE
    or MARK_AS_OVER_ANNOTATED (likely from overexpression/HT).
  • IGF receptor signaling (IBA + IMP) -> KEEP_AS_NON_CORE (legacy GRB10 role).

Pn Notes

(GIGYF2-pn-notes.md)

GIGYF2 PN Consistency Notes

  • Generated: 2026-06-18
  • Project: PROTEOSTASIS
  • Scope: PN consistency rereview against local AIGR review and available deep-research artifacts
  • UniProt: Q6Y7W6
  • 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: GIGYF2 (GRB10-interacting GYF protein 2; TNRC15) is the principal scaffold of the 4EHP-GYF2 translational-repressor complex. Through an N-terminal 4EHP-binding motif it binds the non-canonical cap-binding protein 4EHP (EIF4E2), which occupies the mRNA 5' cap but cannot recruit eIF4G, thereby blocking cap-dependent translation initiation. Its central GYF domain bridges EIF4E2 to RNA-associated repressors, including the AU-rich-element protein ZFP36/tristetraprolin, the miRNA-pathway Argonaute AGO2/TNRC6 machinery, and the collided-ribosome sensor E3 ligase ZNF598, and it recruits the DEAD-box helicase/decapping effector DDX6, coupling translational repression to mRNA destabilization and decay. A major role is in ribosome-associated quality control: on mRNAs that cause ribosome stalling, GIGYF2-EIF4E2 impose a negative-feedback loop that suppresses further initiation, reducing translational load and working in parallel with degradation of the stalled nascent chain. The 4EHP-GIGYF2 complex is essential for mammalian embryonic development, and compromised GIGYF2 function causes neurodevelopmental and neuropsychiatric phenotypes; the gene lies at the PARK11 locus (Parkinson disease 11), although its causal role in Parkinson disease is unclear. GIGYF2 is predominantly cytosolic and also localizes to stress granules, P-bodies and neuronal perikarya/proximal dendrites; SARS-CoV-2 nsp2 co-opts GIGYF2 to repress interferon (IFNB1) translation. A separate legacy role, via the GRB10 adapter, modulates IGF-1/insulin receptor signaling.
  • Existing/core annotation action counts: ACCEPT: 16; KEEP_AS_NON_CORE: 22; MARK_AS_OVER_ANNOTATED: 4; MODIFY: 2

PN Consistency Summary

  • Consistency: Strong and mutually consistent. Deep research, notes, and review agree GIGYF2 is the principal scaffold of the 4EHP-GYF2 repressor complex: its 4EHP-binding motif tethers EIF4E2 to the cap, its GYF domain bridges ZFP36/TTP, AGO2/TNRC6, ZNF598 and DDX6, coupling translational repression to mRNA decay; a major role is RQC negative-feedback on stalled-ribosome mRNAs. Review ACCEPTs GO:0045947 (negative reg translational initiation, IDA), GO:0072344 (rescue of stalled cytosolic ribosome, IDA), GO:0000900 (translation repressor activity), GO:0060090 (adaptor), and MODIFYs protein bindingβ†’GO:0008190 (eIF4E binding). All directly encode the RQC-coupled repression the PN node targets. No contradictions.
  • PN story / NEW pressure: PN asserts only GO:0006515 (RQC umbrella, new_to_goa, verified real). The review already captures the RQC role more specifically via GO:0072344 (IDA, PMID:32726578) plus GO:0045947. GO:0006515 is a broad umbrella over these. Already captured (more precisely); GO:0006515 adds no function the review lacks and does not over-reach (GIGYF2's RQC role is directly evidenced).
  • Evidence alignment: PN dossier lists no reference titles for GIGYF2; alignment is via projected GO:0006515. Review's RQC PMIDs (32726578 RQC negative feedback; 33053355 translation-coupled decay; 31439631 complex assembly; 22751931 development) all anchor the same RQC/repression biology the PN node encodes. No divergence.
  • Verdict: Fully consistent; PN RQC story already captured more precisely (GO:0072344 + GO:0045947 + GO:0000900). GO:0006515 is a defensible umbrella, not an over-reach. No edits warranted.

Full Consistency Review

  • UniProt: Q6Y7W6 Β· batch: proteostasis-batch-2026-06-07c Β· review status: COMPLETE
  • PN placement: Translation|Cytosolic translation|Ribosome-associated QC|other RQC processes ; PN-node mapping: RQC type=no_mapping; RQC group=mappedβ†’GO:0006515; class/branch context_only (GO:0002181/GO:0006412 too_broad).
  • Consistency: Strong and mutually consistent. Deep research, notes, and review agree GIGYF2 is the principal scaffold of the 4EHP-GYF2 repressor complex: its 4EHP-binding motif tethers EIF4E2 to the cap, its GYF domain bridges ZFP36/TTP, AGO2/TNRC6, ZNF598 and DDX6, coupling translational repression to mRNA decay; a major role is RQC negative-feedback on stalled-ribosome mRNAs. Review ACCEPTs GO:0045947 (negative reg translational initiation, IDA), GO:0072344 (rescue of stalled cytosolic ribosome, IDA), GO:0000900 (translation repressor activity), GO:0060090 (adaptor), and MODIFYs protein bindingβ†’GO:0008190 (eIF4E binding). All directly encode the RQC-coupled repression the PN node targets. No contradictions.
  • PN story / NEW pressure: PN asserts only GO:0006515 (RQC umbrella, new_to_goa, verified real). The review already captures the RQC role more specifically via GO:0072344 (IDA, PMID:32726578) plus GO:0045947. GO:0006515 is a broad umbrella over these. Already captured (more precisely); GO:0006515 adds no function the review lacks and does not over-reach (GIGYF2's RQC role is directly evidenced).
  • Mapping strategy: RQC groupβ†’GO:0006515 is an acceptable umbrella over the review's GO:0072344/GO:0045947. No mapping change required. The class/branch context_only demotions (too_broad GO:0002181/GO:0006412) are correct. GIGYF2 is the better-evidenced paralog (direct IDA for GO:0072344); the GIGYF1 review lacks GO:0072344, a paralog asymmetry to flag on the GIGYF1 side rather than here.
  • Evidence alignment: PN dossier lists no reference titles for GIGYF2; alignment is via projected GO:0006515. Review's RQC PMIDs (32726578 RQC negative feedback; 33053355 translation-coupled decay; 31439631 complex assembly; 22751931 development) all anchor the same RQC/repression biology the PN node encodes. No divergence.
  • Verdict: Fully consistent; PN RQC story already captured more precisely (GO:0072344 + GO:0045947 + GO:0000900). GO:0006515 is a defensible umbrella, not an over-reach. No edits warranted.

PN Dossier Context

  • review_batch: proteostasis-batch-2026-06-07c
  • review_yaml: genes/human/GIGYF2/GIGYF2-ai-review.yaml
  • PN workbook rows: 1

PN row 1: Translation | Cytosolic translation | Ribosome-associated QC | other RQC processes

  • UniProt: Q6Y7W6
  • 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 (1)

  • 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.

πŸ“„ View Raw YAML

 
id: Q6Y7W6
gene_symbol: GIGYF2
product_type: PROTEIN
status: COMPLETE
taxon:
  id: NCBITaxon:9606
  label: Homo sapiens
description: >-
  GIGYF2 (GRB10-interacting GYF protein 2; TNRC15) is the principal scaffold of the
  4EHP-GYF2 translational-repressor complex. Through an N-terminal 4EHP-binding motif
  it binds the non-canonical cap-binding protein 4EHP (EIF4E2), which occupies the
  mRNA 5' cap but cannot recruit eIF4G, thereby blocking cap-dependent translation
  initiation. Its central GYF domain bridges EIF4E2 to RNA-associated repressors,
  including the AU-rich-element protein ZFP36/tristetraprolin, the miRNA-pathway
  Argonaute AGO2/TNRC6 machinery, and the collided-ribosome sensor E3 ligase ZNF598,
  and it recruits the DEAD-box helicase/decapping effector DDX6, coupling translational
  repression to mRNA destabilization and decay. A major role is in ribosome-associated
  quality control: on mRNAs that cause ribosome stalling, GIGYF2-EIF4E2 impose a
  negative-feedback loop that suppresses further initiation, reducing translational
  load and working in parallel with degradation of the stalled nascent chain. The
  4EHP-GIGYF2 complex is essential for mammalian embryonic development, and compromised
  GIGYF2 function causes neurodevelopmental and neuropsychiatric phenotypes; the gene
  lies at the PARK11 locus (Parkinson disease 11), although its causal role in Parkinson
  disease is unclear. GIGYF2 is predominantly cytosolic and also localizes to stress
  granules, P-bodies and neuronal perikarya/proximal dendrites; SARS-CoV-2 nsp2 co-opts
  GIGYF2 to repress interferon (IFNB1) translation. A separate legacy role, via the
  GRB10 adapter, modulates IGF-1/insulin receptor signaling.
existing_annotations:
- term:
    id: GO:0000900
    label: mRNA regulatory element binding translation repressor activity
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: enables
  review:
    summary: >-
      Captures GIGYF2's role as a sequence-/element-directed translational repressor:
      it is recruited by RNA-binding adaptors (ZFP36/TTP, TNRC6/AGO2) to specific mRNA
      elements and represses their translation via 4EHP. Well supported and core.
    action: ACCEPT
    reason: >-
      GIGYF2 bridges EIF4E2 to element-binding proteins (e.g. ZFP36/TTP on AU-rich
      elements) to repress translation of specific transcripts, consistent with this MF.
    supported_by:
    - reference_id: file:human/GIGYF2/GIGYF2-uniprot.txt
      supporting_text: acts as a factor that bridges EIF4E2 to ZFP36/TTP, linking
    - reference_id: PMID:27157137
      supporting_text: upon tethering to a reporter mRNA, GIGYF2 exhibits strong, dose-dependent silencing activity, involving both mRNA destabilization and translational repression.
- term:
    id: GO:0045947
    label: negative regulation of translational initiation
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: involved_in
  review:
    summary: >-
      Core function: the 4EHP-GIGYF2 complex represses cap-dependent translation
      initiation. Strongly supported phylogenetically and experimentally.
    action: ACCEPT
    reason: >-
      UniProt and primary literature establish the 4EHP-GYF2 complex as a repressor of
      translation initiation.
    supported_by:
    - reference_id: file:human/GIGYF2/GIGYF2-uniprot.txt
      supporting_text: Key component of the 4EHP-GYF2 complex, a multiprotein
- term:
    id: GO:0016020
    label: membrane
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: is_active_in
  review:
    summary: >-
      Broad 'membrane' localization, phylogenetically inferred. GIGYF2 is a cytosolic
      mRNA-associated protein; any membrane association is peripheral (e.g. with
      membrane-associated translation sites or vesicles) and not its site of action.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      GIGYF2 has no membrane-spanning domain; the informative localizations are cytosol,
      stress granules and P-bodies. The generic 'membrane' is_active_in is not supported
      as a functional site.
    supported_by:
    - reference_id: file:human/GIGYF2/GIGYF2-uniprot.txt
      supporting_text: Key component of the 4EHP-GYF2 complex, a multiprotein
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: is_active_in
  review:
    summary: >-
      GIGYF2 acts in the cytosol on translating mRNAs. Well supported and consistent
      with IDA evidence.
    action: ACCEPT
    reason: >-
      Cytosolic activity is expected for a translational-repression/mRNA-decay adaptor
      and is supported by direct localization data.
    supported_by:
    - reference_id: file:human/GIGYF2/GIGYF2-uniprot.txt
      supporting_text: assists ribosome-associated
- term:
    id: GO:0031982
    label: vesicle
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: is_active_in
  review:
    summary: >-
      Vesicle localization, phylogenetically inferred. GIGYF2 is found in endosomal
      compartments in brain, but vesicle is not its primary functional site.
    action: KEEP_AS_NON_CORE
    reason: >-
      GIGYF2 was reported in endosomal compartments in brain (PMID:20670374); a
      vesicle/endosome association is plausible but peripheral to its translational
      repression role.
    supported_by:
    - reference_id: PMID:20670374
      supporting_text: GIGYF2 is present in endosomal compartments in the mammalian brains and enhances IGF-1-induced ERK1/2 activation.
- term:
    id: GO:0043204
    label: perikaryon
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: is_active_in
  review:
    summary: >-
      Neuronal perikaryon localization, phylogenetically inferred and supported by IDA
      in brain. Relevant to GIGYF2's neuronal roles.
    action: KEEP_AS_NON_CORE
    reason: >-
      GIGYF2 localizes to neuronal perikarya and proximal dendrites (PMID:20670374);
      a cell-type-specific localization rather than a core molecular site.
    supported_by:
    - reference_id: PMID:20670374
      supporting_text: localised in neuronal perikarya and proximal dendrites.
- term:
    id: GO:0048009
    label: insulin-like growth factor receptor signaling pathway
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: involved_in
  review:
    summary: >-
      Legacy GRB10-linked role modulating IGF-1 receptor signaling. Real but secondary
      to the translational-repression/RQC function.
    action: KEEP_AS_NON_CORE
    reason: >-
      GIGYF2 enhances IGF-1-induced ERK signaling via GRB10, but the dominant, broadly
      conserved function is translational repression in the 4EHP-GYF2 complex.
    supported_by:
    - reference_id: PMID:20670374
      supporting_text: enhances IGF-1-induced ERK1/2 activation.
- term:
    id: GO:1990635
    label: proximal dendrite
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: is_active_in
  review:
    summary: >-
      Proximal dendrite localization, supported by IDA in neurons. Relevant to local
      translational control in dendrites.
    action: KEEP_AS_NON_CORE
    reason: >-
      GIGYF2 localizes to proximal dendrites of neurons (PMID:20670374), consistent with
      a role in local translational repression; a cell-type-specific site.
    supported_by:
    - reference_id: PMID:20670374
      supporting_text: localised in neuronal perikarya and proximal dendrites.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:15161933
  qualifier: enables
  review:
    summary: >-
      Generic IPI protein-binding annotation. Records an interaction but the term is
      uninformative; informative interactions (EIF4E2, DDX6) are captured elsewhere.
    action: KEEP_AS_NON_CORE
    reason: >-
      'protein binding' does not convey GIGYF2's molecular function.
    supported_by:
    - reference_id: file:human/GIGYF2/GIGYF2-goa.tsv
      supporting_text: PMID:15161933
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:28698298
  qualifier: enables
  review:
    summary: >-
      Generic IPI protein-binding annotation from a ubiquitin-signaling interaction
      dataset. Uninformative as a molecular function.
    action: KEEP_AS_NON_CORE
    reason: >-
      Records a real interaction but the generic term is not elevated to core.
    supported_by:
    - reference_id: file:human/GIGYF2/GIGYF2-goa.tsv
      supporting_text: PMID:28698298
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:35271311
  qualifier: enables
  review:
    summary: >-
      Generic IPI protein-binding annotation. Uninformative as a molecular function.
    action: KEEP_AS_NON_CORE
    reason: >-
      Records a real interaction but the generic term provides no functional insight.
    supported_by:
    - reference_id: file:human/GIGYF2/GIGYF2-goa.tsv
      supporting_text: PMID:35271311
- term:
    id: GO:0005737
    label: cytoplasm
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: located_in
  review:
    summary: >-
      Cytoplasmic localization (IEA). Consistent with the well-established cytosolic
      activity of GIGYF2.
    action: ACCEPT
    reason: >-
      GIGYF2 is a cytoplasmic mRNA-associated protein; cytoplasm localization is
      well supported.
    supported_by:
    - reference_id: file:human/GIGYF2/GIGYF2-uniprot.txt
      supporting_text: assists ribosome-associated
- term:
    id: GO:0016020
    label: membrane
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: located_in
  review:
    summary: >-
      Generic 'membrane' localization (IEA). GIGYF2 is not an integral membrane protein.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      No transmembrane domain; the informative localizations are cytosol, stress
      granules and P-bodies.
    supported_by:
    - reference_id: file:human/GIGYF2/GIGYF2-uniprot.txt
      supporting_text: Key component of the 4EHP-GYF2 complex, a multiprotein
- term:
    id: GO:0031982
    label: vesicle
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: located_in
  review:
    summary: >-
      Vesicle localization (IEA), corroborated by endosomal localization in brain.
    action: KEEP_AS_NON_CORE
    reason: >-
      Peripheral vesicle/endosome association reported in neurons; not the core site.
    supported_by:
    - reference_id: PMID:20670374
      supporting_text: GIGYF2 is present in endosomal compartments in the mammalian brains and enhances IGF-1-induced ERK1/2 activation.
- term:
    id: GO:0043204
    label: perikaryon
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: located_in
  review:
    summary: >-
      Perikaryon localization (IEA), corroborated by IDA in neurons.
    action: KEEP_AS_NON_CORE
    reason: >-
      Cell-type-specific neuronal localization, supported experimentally.
    supported_by:
    - reference_id: PMID:20670374
      supporting_text: localised in neuronal perikarya and proximal dendrites.
- term:
    id: GO:1990635
    label: proximal dendrite
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: located_in
  review:
    summary: >-
      Proximal dendrite localization (IEA), corroborated by IDA in neurons.
    action: KEEP_AS_NON_CORE
    reason: >-
      Cell-type-specific neuronal localization, supported experimentally.
    supported_by:
    - reference_id: PMID:20670374
      supporting_text: localised in neuronal perikarya and proximal dendrites.
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: IDA
  original_reference_id: GO_REF:0000052
  qualifier: located_in
  review:
    summary: >-
      Direct (immunofluorescence) cytosol localization. Consistent with GIGYF2's
      cytosolic activity.
    action: ACCEPT
    reason: >-
      Cytosolic localization is experimentally supported and matches its function.
    supported_by:
    - reference_id: file:human/GIGYF2/GIGYF2-uniprot.txt
      supporting_text: assists ribosome-associated
- 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-GIGYF2 co-translational
      mRNA-decay complex. The biology (decay of translated, ribosome-stalled mRNAs) 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;
      a mature-mRNA catabolic term better reflects the evidence.
    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:0045947
    label: negative regulation of translational initiation
  evidence_type: IDA
  original_reference_id: PMID:32726578
  qualifier: involved_in
  review:
    summary: >-
      Direct evidence that GIGYF2 (with 4EHP) inhibits translation initiation on
      ribosome-stalling mRNAs as a negative-feedback RQC mechanism. Core function.
    action: ACCEPT
    reason: >-
      CRISPR screening and reporter assays show GIGYF2/4EHP specifically inhibit
      initiation on defective messages.
    supported_by:
    - reference_id: PMID:32726578
      supporting_text: This negative feedback loop is mediated by two translation inhibitors, GIGYF2 and 4EHP.
- term:
    id: GO:0045947
    label: negative regulation of translational initiation
  evidence_type: IDA
  original_reference_id: PMID:35878012
  qualifier: involved_in
  review:
    summary: >-
      Direct evidence that GIGYF2/4EHP repress translation initiation of IFNB1 mRNA,
      co-opted by SARS-CoV-2 nsp2. Supports the core repressor function.
    action: ACCEPT
    reason: >-
      GIGYF2/4EHP repress Ifnb1 translation; nsp2 enhances GIGYF2-EIF4E2 binding to
      increase this repression.
    supported_by:
    - reference_id: PMID:35878012
      supporting_text: Here, we document a mechanism by which the NSP2 protein impedes IFN-Ξ² expression through translational repression of Ifnb1 mRNA by coopting the GIGYF2/4EHP complex
- term:
    id: GO:0060090
    label: molecular adaptor activity
  evidence_type: IDA
  original_reference_id: PMID:32726578
  qualifier: enables
  review:
    summary: >-
      GIGYF2 functions as a molecular adaptor that bridges EIF4E2 to RNA-associated
      factors and ZNF598/RQC machinery. Core molecular function.
    action: ACCEPT
    reason: >-
      GIGYF2 bridges EIF4E2 to ZFP36/TTP, DDX6 and the RQC apparatus; an adaptor MF is
      appropriate and informative.
    supported_by:
    - reference_id: file:human/GIGYF2/GIGYF2-uniprot.txt
      supporting_text: acts as a factor that bridges EIF4E2 to ZFP36/TTP, linking
- term:
    id: GO:0060090
    label: molecular adaptor activity
  evidence_type: IDA
  original_reference_id: PMID:35878012
  qualifier: enables
  review:
    summary: >-
      GIGYF2 adaptor activity bridging EIF4E2 and nsp2/RNA factors to repress IFNB1.
      Supports the adaptor MF.
    action: ACCEPT
    reason: >-
      nsp2 co-opts the GIGYF2 adaptor to recruit 4EHP to IFNB1 mRNA, consistent with a
      bridging/adaptor function.
    supported_by:
    - reference_id: PMID:35878012
      supporting_text: Here, we document a mechanism by which the NSP2 protein impedes IFN-Ξ² expression through translational repression of Ifnb1 mRNA by coopting the GIGYF2/4EHP complex
- 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: >-
      GIGYF2/4EHP repress IFNB1 (type I IFN) translation; this is the basis of nsp2's
      immune evasion. A genuine, though context-specific, role.
    action: KEEP_AS_NON_CORE
    reason: >-
      The IFN-repression role is a specific consequence of GIGYF2's general translational
      repression activity acting on IFNB1 mRNA, exploited during SARS-CoV-2 infection;
      relevant but not the core, ubiquitous function.
    supported_by:
    - reference_id: PMID:35878012
      supporting_text: Here, we document a mechanism by which the NSP2 protein impedes IFN-Ξ² expression through translational repression of Ifnb1 mRNA by coopting the GIGYF2/4EHP complex
- term:
    id: GO:0072344
    label: rescue of stalled cytosolic ribosome
  evidence_type: IDA
  original_reference_id: PMID:32726578
  qualifier: involved_in
  review:
    summary: >-
      GIGYF2/4EHP participate in ribosome-associated quality control by suppressing new
      initiation on mRNAs that stall ribosomes, working in concert with RQC degradation
      pathways. Core RQC function.
    action: ACCEPT
    reason: >-
      Direct evidence places GIGYF2/4EHP in the RQC response to stalled ribosomes, acting
      in parallel with degradation of the stalled nascent chain.
    supported_by:
    - reference_id: PMID:32726578
      supporting_text: GIGYF2 and 4EHP Inhibit Translation Initiation of Defective Messenger RNAs to Assist Ribosome-Associated Quality Control.
    - reference_id: file:human/GIGYF2/GIGYF2-uniprot.txt
      supporting_text: assists ribosome-associated quality control
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:31439631
  qualifier: enables
  review:
    summary: >-
      IPI annotation capturing the structurally defined direct interactions of GIGYF2
      with EIF4E2, ZFP36/TTP and DDX6. Functionally central but 'protein binding' is
      too generic.
    action: MODIFY
    reason: >-
      The interactions defined here (EIF4E2 via 4EHP-binding motif; DDX6 via a dedicated
      motif; TTP via P-P-P-P-G repeats) underlie translational repression; a specific
      eIF4E-binding / repression MF is more informative than generic protein binding.
    proposed_replacement_terms:
    - id: GO:0008190
      label: eukaryotic initiation factor 4E binding
    supported_by:
    - reference_id: file:human/GIGYF2/GIGYF2-uniprot.txt
      supporting_text: Interacts (via the 4EHP-binding motif) with EIF4E2;
- term:
    id: GO:0045296
    label: cadherin binding
  evidence_type: HDA
  original_reference_id: PMID:25468996
  qualifier: enables
  review:
    summary: >-
      'cadherin binding' from a high-throughput proximity/affinity proteomics dataset.
      There is no functional evidence that cadherin binding is part of GIGYF2 biology.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      This term commonly arises as an artifact of HT BioID/AP-MS proximity datasets and
      does not reflect a characterized GIGYF2 function.
    supported_by:
    - reference_id: file:human/GIGYF2/GIGYF2-goa.tsv
      supporting_text: PMID:25468996
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:20878056
  qualifier: enables
  review:
    summary: >-
      Generic protein-binding annotation from an EGFR-Akt/RQCD1 study. Uninformative as
      a molecular function.
    action: KEEP_AS_NON_CORE
    reason: >-
      Records interactions in a signaling-network context but the generic term is not
      elevated.
    supported_by:
    - reference_id: PMID:20878056
      supporting_text: Critical involvement of RQCD1 in the EGFR-Akt pathway in mammary carcinogenesis.
- term:
    id: GO:0032991
    label: protein-containing complex
  evidence_type: IDA
  original_reference_id: PMID:20878056
  qualifier: part_of
  review:
    summary: >-
      Generic complex membership. GIGYF2 is a bona fide complex component (4EHP-GYF2),
      but the top-level term is uninformative.
    action: KEEP_AS_NON_CORE
    reason: >-
      The specific complex (4EHP-GIGYF2-DDX6/ZNF598) is captured by the functional
      annotations; 'protein-containing complex' conveys no specific information.
    supported_by:
    - reference_id: PMID:20878056
      supporting_text: Critical involvement of RQCD1 in the EGFR-Akt pathway in mammary carcinogenesis.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:20670374
  qualifier: enables
  review:
    summary: >-
      Generic protein-binding annotation from the brain IGF/endosome study. Uninformative
      as a molecular function.
    action: KEEP_AS_NON_CORE
    reason: >-
      Records a real interaction but the generic term is not elevated.
    supported_by:
    - reference_id: PMID:20670374
      supporting_text: GIGYF2 is present in endosomal compartments in the mammalian brains and enhances IGF-1-induced ERK1/2 activation.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:20696395
  qualifier: enables
  review:
    summary: >-
      Generic protein-binding annotation from the GYF-domain proline-rich-sequence
      recognition study. The specific MF (proline-rich region binding) is captured
      separately.
    action: KEEP_AS_NON_CORE
    reason: >-
      Records the GYF-domain PRS interaction; the informative MF is GO:0070064.
    supported_by:
    - reference_id: PMID:20696395
      supporting_text: Conserved beta-hairpin recognition by the GYF domains of Smy2 and GIGYF2 in mRNA surveillance and vesicular transport complexes.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:27157137
  qualifier: enables
  review:
    summary: >-
      Generic protein-binding annotation from the AGO2/miRNA silencing study. The
      functional outcome (silencing/destabilization) is captured by other terms.
    action: KEEP_AS_NON_CORE
    reason: >-
      Records the GIGYF2-AGO2 interaction; the generic term is not elevated.
    supported_by:
    - reference_id: PMID:27157137
      supporting_text: upon tethering to a reporter mRNA, GIGYF2 exhibits strong, dose-dependent silencing activity, involving both mRNA destabilization and translational repression.
- term:
    id: GO:0005768
    label: endosome
  evidence_type: IDA
  original_reference_id: PMID:20670374
  qualifier: located_in
  review:
    summary: >-
      Endosome localization in brain (IDA). A genuine but peripheral localization.
    action: KEEP_AS_NON_CORE
    reason: >-
      GIGYF2 was found in endosomal compartments in brain; relevant to its neuronal/IGF
      role but not its core translational-repression site.
    supported_by:
    - reference_id: PMID:20670374
      supporting_text: GIGYF2 is present in endosomal compartments in the mammalian brains and enhances IGF-1-induced ERK1/2 activation.
- term:
    id: GO:0005783
    label: endoplasmic reticulum
  evidence_type: IDA
  original_reference_id: PMID:20696395
  qualifier: located_in
  review:
    summary: >-
      ER localization reported alongside GYF-domain studies. GIGYF2 is mainly cytosolic;
      ER association is likely peripheral (e.g. at ER-bound translation sites).
    action: KEEP_AS_NON_CORE
    reason: >-
      Peripheral ER association is plausible for a translation-associated factor but is
      not its defining site.
    supported_by:
    - reference_id: PMID:20696395
      supporting_text: Conserved beta-hairpin recognition by the GYF domains of Smy2 and GIGYF2 in mRNA surveillance and vesicular transport complexes.
- term:
    id: GO:0005794
    label: Golgi apparatus
  evidence_type: IDA
  original_reference_id: PMID:20696395
  qualifier: located_in
  review:
    summary: >-
      Golgi localization reported alongside GYF-domain studies. GIGYF2 is mainly
      cytosolic; Golgi association is peripheral.
    action: KEEP_AS_NON_CORE
    reason: >-
      Not the defining functional site; a peripheral localization.
    supported_by:
    - reference_id: PMID:20696395
      supporting_text: Conserved beta-hairpin recognition by the GYF domains of Smy2 and GIGYF2 in mRNA surveillance and vesicular transport complexes.
- term:
    id: GO:0010494
    label: cytoplasmic stress granule
  evidence_type: IDA
  original_reference_id: PMID:20696395
  qualifier: located_in
  review:
    summary: >-
      Stress granule localization (IDA). Consistent with GIGYF2's role in translational
      repression and mRNA storage/decay.
    action: ACCEPT
    reason: >-
      GIGYF2 partitions into stress granules, consistent with its repressed-mRNP
      associations.
    supported_by:
    - reference_id: PMID:20696395
      supporting_text: Conserved beta-hairpin recognition by the GYF domains of Smy2 and GIGYF2 in mRNA surveillance and vesicular transport complexes.
- term:
    id: GO:0016441
    label: post-transcriptional gene silencing
  evidence_type: IDA
  original_reference_id: PMID:27157137
  qualifier: involved_in
  review:
    summary: >-
      GIGYF2 is a silencing effector in the miRNA/AGO2 pathway, repressing translation
      and destabilizing target mRNAs when tethered.
    action: ACCEPT
    reason: >-
      Tethering assays show strong, dose-dependent silencing by GIGYF2 via the
      AGO2/miRNA pathway.
    supported_by:
    - reference_id: PMID:27157137
      supporting_text: upon tethering to a reporter mRNA, GIGYF2 exhibits strong, dose-dependent silencing activity, involving both mRNA destabilization and translational repression.
- term:
    id: GO:0043204
    label: perikaryon
  evidence_type: IDA
  original_reference_id: PMID:20670374
  qualifier: located_in
  review:
    summary: >-
      Direct neuronal perikaryon localization. Relevant to neuronal function.
    action: KEEP_AS_NON_CORE
    reason: >-
      Cell-type-specific neuronal localization supported by direct evidence.
    supported_by:
    - reference_id: PMID:20670374
      supporting_text: localised in neuronal perikarya and proximal dendrites.
- term:
    id: GO:0048009
    label: insulin-like growth factor receptor signaling pathway
  evidence_type: IMP
  original_reference_id: PMID:20670374
  qualifier: involved_in
  review:
    summary: >-
      IMP evidence that GIGYF2 modulates IGF-1 receptor/ERK signaling. Legacy GRB10-linked
      role; secondary to translational repression.
    action: KEEP_AS_NON_CORE
    reason: >-
      GIGYF2 enhances IGF-1-induced ERK activation, but its dominant conserved function
      is translational repression.
    supported_by:
    - reference_id: PMID:20670374
      supporting_text: enhances IGF-1-induced ERK1/2 activation.
- term:
    id: GO:0061157
    label: mRNA destabilization
  evidence_type: IDA
  original_reference_id: PMID:27157137
  qualifier: involved_in
  review:
    summary: >-
      GIGYF2 destabilizes target mRNAs (in addition to repressing their translation),
      consistent with coupling repression to decay via DDX6/decapping.
    action: ACCEPT
    reason: >-
      Tethered GIGYF2 causes mRNA destabilization; this is a genuine functional output.
    supported_by:
    - reference_id: PMID:27157137
      supporting_text: upon tethering to a reporter mRNA, GIGYF2 exhibits strong, dose-dependent silencing activity, involving both mRNA destabilization and translational repression.
- term:
    id: GO:0070064
    label: proline-rich region binding
  evidence_type: IDA
  original_reference_id: PMID:20696395
  qualifier: enables
  review:
    summary: >-
      The GYF domain of GIGYF2 recognizes proline-rich sequences in partner proteins,
      mediating recruitment to mRNA-surveillance/transport complexes. Informative MF.
    action: ACCEPT
    reason: >-
      Direct structural evidence that the GIGYF2 GYF domain binds proline-rich sequences
      (PRS), the basis of its adaptor interactions.
    supported_by:
    - reference_id: PMID:20696395
      supporting_text: Conserved beta-hairpin recognition by the GYF domains of Smy2 and GIGYF2 in mRNA surveillance and vesicular transport complexes.
- term:
    id: GO:1990635
    label: proximal dendrite
  evidence_type: IDA
  original_reference_id: PMID:20670374
  qualifier: located_in
  review:
    summary: >-
      Direct proximal-dendrite localization in neurons.
    action: KEEP_AS_NON_CORE
    reason: >-
      Cell-type-specific neuronal localization supported by direct evidence; consistent
      with local translational control.
    supported_by:
    - reference_id: PMID:20670374
      supporting_text: localised in neuronal perikarya and proximal dendrites.
- term:
    id: GO:0016020
    label: membrane
  evidence_type: HDA
  original_reference_id: PMID:19946888
  qualifier: located_in
  review:
    summary: >-
      'membrane' from a high-throughput proteomics dataset. GIGYF2 is not an integral
      membrane protein.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      No transmembrane domain; HT membrane-fraction co-purification does not establish a
      functional membrane localization.
    supported_by:
    - reference_id: file:human/GIGYF2/GIGYF2-goa.tsv
      supporting_text: PMID:19946888
- 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. Consistent with
      GIGYF2's association with target mRNAs and ribosomes.
    action: ACCEPT
    reason: >-
      GIGYF2 was identified as an mRNA-bound protein, consistent with its co-translational
      binding to target transcripts.
    supported_by:
    - reference_id: file:human/GIGYF2/GIGYF2-goa.tsv
      supporting_text: PMID:22681889
- 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;
      its disruption increases translation and causes perinatal lethality in mice. Core.
    action: ACCEPT
    reason: >-
      Disruption of the m4EHP-GIGYF2 complex leads to increased translation, directly
      demonstrating GIGYF2's negative regulation of translation.
    supported_by:
    - reference_id: PMID:22751931
      supporting_text: Disruption of the m4EHP-GIGYF2 complex leads to increased translation and perinatal lethality in mice.
core_functions:
- description: >-
    GIGYF2 binds the non-canonical cap-binding protein 4EHP/EIF4E2 via its N-terminal
    4EHP-binding motif, the molecular basis for cap sequestration and repression of
    cap-dependent translation initiation.
  molecular_function:
    id: GO:0008190
    label: eukaryotic initiation factor 4E binding
  locations:
  - id: GO:0005829
    label: cytosol
  supported_by:
  - reference_id: file:human/GIGYF2/GIGYF2-uniprot.txt
    supporting_text: Interacts (via the 4EHP-binding motif) with EIF4E2;
- description: >-
    GIGYF2 acts as a molecular adaptor that bridges EIF4E2 to RNA-associated repressors
    (ZFP36/TTP, AGO2/TNRC6), the decapping helicase DDX6, and the collided-ribosome
    sensor ZNF598, organizing the 4EHP-GYF2 repression/decay module.
  molecular_function:
    id: GO:0060090
    label: molecular adaptor activity
  locations:
  - id: GO:0005829
    label: cytosol
  supported_by:
  - reference_id: file:human/GIGYF2/GIGYF2-uniprot.txt
    supporting_text: acts as a factor that bridges EIF4E2 to ZFP36/TTP, linking
- description: >-
    As an element-directed translational repressor, GIGYF2 represses initiation of
    specific mRNAs and, on ribosome-stalling messages, imposes a negative-feedback loop
    that suppresses further initiation as part of ribosome-associated quality control.
  molecular_function:
    id: GO:0000900
    label: mRNA regulatory element binding translation repressor activity
  locations:
  - id: GO:0005829
    label: cytosol
  - id: GO:0010494
    label: cytoplasmic stress granule
  supported_by:
  - reference_id: PMID:32726578
    supporting_text: This negative feedback loop is mediated by two translation inhibitors, GIGYF2 and 4EHP.
proposed_new_terms: []
suggested_questions:
- question: Which endogenous mRNAs depend on GIGYF2 (versus GIGYF1) for RQC-coupled repression, and how is target selection partitioned between ZNF598-, TTP- and miRNA-directed recruitment?
- question: How do GIGYF2 loss-of-function variants produce neurodevelopmental/neuropsychiatric phenotypes - via failure of RQC-coupled repression, dysregulated dendritic translation, or altered IGF signaling?
suggested_experiments:
- description: Ribosome profiling plus mRNA stability measurements in GIGYF2 knockout cells (and 4EHP-binding-motif or GYF-domain separation-of-function mutants) to define target mRNAs and the contribution of each interaction.
- description: Reconstitution of the 4EHP-GIGYF2-ZNF598 module on stalled-ribosome substrates to test whether GIGYF2 directly couples collision sensing to initiation shutdown.
references:
- id: GO_REF:0000033
  title: Annotation inferences using phylogenetic trees
  findings: []
- id: GO_REF:0000052
  title: Gene Ontology annotation based on curation of immunofluorescence data
  findings: []
- id: GO_REF:0000107
  title: Automatic transfer of experimentally verified manual GO annotation data to orthologs using Ensembl Compara
  findings: []
- id: PMID:15161933
  title: Comprehensive proteomic analysis of interphase and mitotic 14-3-3-binding proteins.
  findings: []
- id: PMID:19946888
  title: Defining the membrane proteome of NK cells.
  findings: []
- id: PMID:20670374
  title: GIGYF2 is present in endosomal compartments in the mammalian brains and enhances IGF-1-induced ERK1/2 activation.
  findings:
  - statement: GIGYF2 localizes to endosomal compartments, neuronal perikarya and proximal dendrites, and enhances IGF-1-induced ERK1/2 activation; mutant GIGYF2 did not localize to Lewy bodies.
    reference_section_type: ABSTRACT
- id: PMID:20696395
  title: Conserved beta-hairpin recognition by the GYF domains of Smy2 and GIGYF2 in mRNA surveillance and vesicular transport complexes.
  findings:
  - statement: The GYF domain of GIGYF2 recognizes proline-rich sequences via a conserved beta-hairpin, mediating its assembly into mRNA-surveillance and vesicular-transport complexes.
    reference_section_type: ABSTRACT
- id: PMID:20878056
  title: Critical involvement of RQCD1 in the EGFR-Akt pathway in mammary carcinogenesis.
  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.
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: "Cached publications/PMID_22751931.md title matches YAML title and body confirms the 4EHP-GIGYF2 translational repressor complex; establishes the core EIF4E2-binding/repression function."
  findings:
  - statement: GIGYF2 directly interacts with m4EHP; this interaction stabilizes both proteins, and disruption of the m4EHP-GIGYF2 complex increases translation and causes perinatal lethality in mice.
    reference_section_type: ABSTRACT
- id: PMID:25468996
  title: E-cadherin interactome complexity and robustness resolved by quantitative proteomics.
  findings: []
- id: PMID:27157137
  title: Post-transcriptional gene silencing activity of human GIGYF2.
  findings:
  - statement: Full-length GIGYF2 coimmunoprecipitates with AGO2 and, when tethered to a reporter mRNA, exhibits strong dose-dependent silencing involving both mRNA destabilization and translational repression.
    reference_section_type: ABSTRACT
- id: PMID:28698298
  title: 'GIGYF1/2 proteins use auxiliary sequences to selectively bind to 4EHP and repress target mRNA expression.'
  findings: []
- id: PMID:31439631
  title: Molecular basis for GIGYF-Me31B complex assembly in 4EHP-mediated translational repression.
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: "Cached publications/PMID_31439631.md title matches; body confirms GIGYF-Me31B/DDX6 direct interaction and crystal structure, supporting the molecular-adaptor core function bridging EIF4E2 to DDX6/ZFP36."
  findings:
  - statement: GIGYF2 interacts directly with EIF4E2 (via the 4EHP-binding motif), with ZFP36/TTP (via P-P-P-P-G repeats), and with DDX6 (via a dedicated motif binding the DDX6 RecA2 domain).
    reference_section_type: RESULTS
- 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 and confirms the RQC-coupled negative-feedback translation-repression mechanism; directly supports core_function GO:0000900 (translation repressor activity). Cited in core_functions supported_by."
  findings:
  - statement: Failed translation triggers GIGYF2/4EHP-mediated inhibition of translation initiation on that message, a negative-feedback RQC mechanism acting in concert with degradation of the stalled nascent polypeptide.
    reference_section_type: ABSTRACT
- id: PMID:33053355
  title: 4EHP and GIGYF1/2 Mediate Translation-Coupled Messenger RNA Decay.
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: "Cached publications/PMID_33053355.md title matches; confirms 4EHP-GIGYF1/2-mediated translation-coupled mRNA decay, corroborating the repression/decay module core function."
  findings:
  - statement: 4EHP-GIGYF1/2 complexes trigger co-translational mRNA decay of transcripts that experience ribosome pausing.
    reference_section_type: ABSTRACT
- 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 binds GIGYF2 and enhances GIGYF2-EIF4E2 association to repress translation of IFNB1 mRNA, dampening the type I interferon response.
    reference_section_type: ABSTRACT
- id: file:human/GIGYF2/GIGYF2-uniprot.txt
  title: UniProt entry Q6Y7W6 (GGYF2_HUMAN)
  findings: []
- id: file:human/GIGYF2/GIGYF2-goa.tsv
  title: GOA annotations for GIGYF2
  findings: []