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-β 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-β 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-β 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: []