id: O75420 gene_symbol: GIGYF1 product_type: PROTEIN status: COMPLETE taxon: id: NCBITaxon:9606 label: Homo sapiens description: >- GIGYF1 (GRB10-interacting GYF protein 1; PERQ1) is a cytosolic adaptor/scaffold protein and the paralog of GIGYF2. Its central GYF domain and N-terminal 4EHP-binding region allow it to nucleate a translational-repression and co-translational mRNA-decay module together with the non-canonical cap-binding protein 4EHP (EIF4E2), the DEAD-box helicase DDX6, and the collided-ribosome sensor E3 ligase ZNF598. By tethering 4EHP to the mRNA 5' cap, GIGYF1 represses cap-dependent translation initiation, and by co-translationally binding transcripts that experience ribosome pausing or stalling it marks them for decay, linking ribosome transit to mRNA turnover. The GYF domain also recruits RNA-associated repressors such as tristetraprolin (TTP) and the miRNA-pathway TNRC6 proteins to specific messages. In a separate, less-characterized legacy role, GIGYF1 was first identified through the GRB10 adapter as a modulator of insulin-like growth factor-1 (IGF-1) receptor and other receptor tyrosine kinase signaling. The protein is largely intrinsically disordered outside its GYF domain and is heavily phosphorylated. existing_annotations: - term: id: GO:0045947 label: negative regulation of translational initiation evidence_type: IBA original_reference_id: GO_REF:0000033 qualifier: involved_in review: summary: >- GIGYF1 tethers the non-canonical cap-binding protein 4EHP/EIF4E2 to mRNA, repressing cap-dependent translation initiation as part of the 4EHP-GIGYF1/2 repressor module. This is well supported and represents a core function. action: ACCEPT reason: >- The 4EHP-GIGYF1/2 complex represses translation and triggers co-translational decay; loss of these proteins fails to reduce target mRNA levels and accumulates ribosome-paused transcripts. The IBA call is consistent with direct experimental evidence on the complex. supported_by: - reference_id: PMID:33053355 supporting_text: >- 4EHP-GIGYF1/2 complexes fail to reduce mRNA levels in the absence of ribosome stalling or upon disruption of their interaction with the cap structure, DDX6, and ZNF598. - reference_id: PMID:31439631 supporting_text: >- These proteins possess an N-terminal 4EHP-binding region (4EHP-BR) and a central compacted GYF domain - term: id: GO:0005829 label: cytosol evidence_type: IBA original_reference_id: GO_REF:0000033 qualifier: is_active_in review: summary: >- GIGYF1 acts in the cytosol, where it associates with ribosomes, the mRNA cap, DDX6 and P-body/decay machinery. The localization is consistent with its translational-repression function. action: ACCEPT reason: >- Cytosolic activity is expected for a translation/mRNA-decay adaptor and is phylogenetically well supported; the complex acts co-translationally on cytoplasmic mRNAs. supported_by: - reference_id: PMID:33053355 supporting_text: >- co-translational binding of GIGYF1/2 to the mRNA marks transcripts with perturbed elongation to decay. - 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: >- GIGYF1 was originally identified via the GRB10 adapter as a modulator of IGF-1 receptor signaling and may increase IGF1R phosphorylation. This is a real but secondary, less-characterized role relative to its translational repression function. action: KEEP_AS_NON_CORE reason: >- UniProt records a GRB10-linked IGF signaling role, but the mechanistic and genetic evidence for GIGYF1's principal cellular function centers on 4EHP/DDX6-mediated translational repression and co-translational mRNA decay. The IGF role is retained as non-core. supported_by: - reference_id: file:human/GIGYF1/GIGYF1-uniprot.txt supporting_text: May increase IGF1 receptor phosphorylation under - 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 an interaction dataset. Records a real interaction but the term is uninformative about function. action: KEEP_AS_NON_CORE reason: >- Bare protein binding does not capture GIGYF1's molecular function; the informative interaction (eIF4E2/EIF4E2) is captured separately as a core MF. supported_by: - reference_id: file:human/GIGYF1/GIGYF1-goa.tsv supporting_text: PMID:28698298 - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:32296183 qualifier: enables review: summary: >- Generic protein-binding annotation derived from a large-scale binary interactome map (HuRI). Uninformative as a molecular function. action: KEEP_AS_NON_CORE reason: >- High-throughput Y2H interactome screen; the many partners listed are not individually validated for GIGYF1 function and the term adds no functional information beyond the curated 4EHP/DDX6 interactions. supported_by: - reference_id: PMID:32296183 supporting_text: A reference map of the human binary protein interactome. - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:33053355 qualifier: enables review: summary: >- Protein-binding annotation from the study establishing the 4EHP-GIGYF1/2 co-translational mRNA-decay complex (interaction with ZNF598). The interaction is functionally meaningful but the generic term is uninformative. action: KEEP_AS_NON_CORE reason: >- The underlying interaction (GIGYF1 with ZNF598, the collided-ribosome sensor) is central to the RQC-coupled decay role, but 'protein binding' is too generic; the function is captured by the eIF4E binding MF and the translation-repression BP. supported_by: - reference_id: PMID:33053355 supporting_text: >- 4EHP-GIGYF1/2 complexes fail to reduce mRNA levels in the absence of ribosome stalling or upon disruption of their interaction with the cap structure, DDX6, and ZNF598. - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:33961781 qualifier: enables review: summary: >- Generic protein-binding annotation from the BioPlex affinity-purification interactome. Records interactions including DDX6 but the term is uninformative. action: KEEP_AS_NON_CORE reason: >- High-throughput AP-MS interactome; the DDX6 interaction it captures is meaningful and covered by the core eIF4E binding / repression functions, but the generic term itself is not elevated. supported_by: - reference_id: PMID:33961781 supporting_text: Dual proteome-scale networks reveal cell-specific remodeling of the human interactome. - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:36950384 qualifier: enables review: summary: >- Generic protein-binding annotation from an interaction-proteomics study in human induced neurons mapping autism-associated networks. Uninformative as a molecular function for GIGYF1. action: KEEP_AS_NON_CORE reason: >- High-throughput interactome dataset; provides no specific functional insight for GIGYF1 beyond a network membership. supported_by: - reference_id: PMID:36950384 supporting_text: Protein interaction studies in human induced neurons indicate convergent biology underlying autism spectrum disorders. - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:38225382 qualifier: enables review: summary: >- Generic protein-binding annotation from an AlphaFold-based interface prediction/validation study. Uninformative as a molecular function. action: KEEP_AS_NON_CORE reason: >- Computational interface discovery dataset; not a specific functional characterization of GIGYF1. supported_by: - reference_id: PMID:38225382 supporting_text: Systematic discovery of protein interaction interfaces using AlphaFold and experimental validation. - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:39251607 qualifier: enables review: summary: >- Generic protein-binding annotation from a systematic post-transcriptional regulatory-module study. Uninformative as a molecular function. action: KEEP_AS_NON_CORE reason: >- Records a real interaction (DDX6) consistent with the repression module but the generic term is not elevated to core. supported_by: - reference_id: PMID:39251607 supporting_text: Systematic identification of post-transcriptional regulatory modules. - 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 GIGYF1's role in the 4EHP-GIGYF1 co-translational mRNA-decay complex. The biology (decay of mature, translated mRNAs that experience ribosome pausing) is correct, but 'pre-mRNA catabolic process' is an imprecise label, since the substrates are mature, ribosome-engaged mRNAs rather than pre-mRNA. action: MODIFY reason: >- The complex triggers co-translational decay of mature mRNAs with ribosome pausing, 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: >- Here, we show that 4EHP-GIGYF1/2 complexes trigger co-translational mRNA decay. Human cells lacking these proteins accumulate mRNAs with prominent ribosome pausing. - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:31439631 qualifier: enables review: summary: >- IPI annotation capturing the direct, structurally defined interaction between GIGYF and the DEAD-box helicase DDX6/Me31B, required for assembly of the 4EHP-GIGYF-DDX6 repressor complex. The interaction is functionally important but 'protein binding' is too generic. action: MODIFY reason: >- A 2.4 A crystal structure defines a GIGYF motif that directly binds the DDX6 RecA2 domain, and this assembly is required for repression. A specific negative-regulation-of-translation MF/BP is more informative than generic protein binding. proposed_replacement_terms: - id: GO:0017148 label: negative regulation of translation supported_by: - reference_id: PMID:31439631 supporting_text: >- we report that GIGYF contains a motif necessary and sufficient for direct interaction with Me31B/DDX6 - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:20878056 qualifier: enables review: summary: >- Generic protein-binding annotation from a study of RQCD1 (CNOT9) in the EGFR-Akt pathway, in which GIGYF1 was identified in associated complexes. Uninformative as a molecular function. action: KEEP_AS_NON_CORE reason: >- Records interactions (EGFR/AKT/GRB10/RQCD1 network) consistent with the legacy receptor-signaling role 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:0008190 label: eukaryotic initiation factor 4E binding evidence_type: IPI original_reference_id: PMID:31439631 qualifier: enables review: summary: >- NEW annotation capturing GIGYF1's defining molecular interaction: direct binding of the non-canonical cap-binding eIF4E-family protein 4EHP/EIF4E2 via its N-terminal 4EHP-binding region. This is the informative replacement for the generic protein-binding annotations and the basis of its translational-repression function. action: NEW reason: >- GIGYF proteins possess a dedicated 4EHP-binding region and the 4EHP-GIGYF interaction is required for translational repression and co-translational mRNA decay; EIF4E2 is a validated curated interactor of GIGYF1 (UniProt IntAct, NbExp=12). supported_by: - reference_id: PMID:31439631 supporting_text: >- These proteins possess an N-terminal 4EHP-binding region (4EHP-BR) and a central compacted GYF domain - reference_id: file:human/GIGYF1/GIGYF1-uniprot.txt supporting_text: "O75420; O60573-1: EIF4E2; NbExp=12; IntAct=EBI-947774, EBI-32715389;" - term: id: GO:0032991 label: protein-containing complex evidence_type: IDA original_reference_id: PMID:20878056 qualifier: part_of review: summary: >- Annotation that GIGYF1 is part of a protein-containing complex. The top-level term is uninformative about which complex. action: KEEP_AS_NON_CORE reason: >- GIGYF1 is a bona fide complex component (4EHP-GIGYF1-DDX6/ZNF598 decay complexes), but the generic 'protein-containing complex' term conveys no specific information. supported_by: - reference_id: PMID:20878056 supporting_text: Critical involvement of RQCD1 in the EGFR-Akt pathway in mammary carcinogenesis. core_functions: - description: >- GIGYF1 binds the non-canonical cap-binding protein 4EHP/EIF4E2 through its N-terminal 4EHP-binding region, tethering it to mRNA to repress 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: PMID:31439631 supporting_text: >- These proteins possess an N-terminal 4EHP-binding region (4EHP-BR) and a central compacted GYF domain - description: >- As the scaffold of the 4EHP-GIGYF1/2 module (with DDX6 and ZNF598), GIGYF1 represses translation and triggers co-translational decay of mRNAs that experience ribosome pausing or stalling, coupling ribosome transit to mRNA turnover. molecular_function: id: GO:0008190 label: eukaryotic initiation factor 4E binding locations: - id: GO:0005829 label: cytosol supported_by: - reference_id: PMID:33053355 supporting_text: >- Here, we show that 4EHP-GIGYF1/2 complexes trigger co-translational mRNA decay. Human cells lacking these proteins accumulate mRNAs with prominent ribosome pausing. directly_involved_in: - id: GO:0045947 label: negative regulation of translational initiation proposed_new_terms: [] suggested_questions: - question: Does GIGYF1 act redundantly with GIGYF2 in co-translational mRNA decay, or do the paralogs have distinct target-mRNA repertoires and tissue contexts? - question: To what extent does GIGYF1 contribute to ZNF598-dependent ribosome-collision quality control versus 4EHP-only translational repression at uncollided mRNAs? suggested_experiments: - description: Ribosome profiling and mRNA-decay measurements in GIGYF1 single-knockout versus GIGYF1/GIGYF2 double-knockout cells to define paralog-specific target mRNAs. - description: Structure-guided separation-of-function mutants (4EHP-binding vs DDX6-binding vs GYF-domain ZNF598/TTP binding) to dissect the contribution of each interaction to repression and decay. references: - id: GO_REF:0000033 title: Annotation inferences using phylogenetic trees findings: [] - id: PMID:20878056 title: Critical involvement of RQCD1 in the EGFR-Akt pathway in mammary carcinogenesis. findings: [] - 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 YAML; defines the molecular basis of GIGYF-4EHP-DDX6 complex assembly in translational repression, supporting the core 4EHP-binding/adaptor and translational-repression functions." findings: - statement: GIGYF contains a motif that directly binds the DDX6/Me31B RecA2 domain, and 4EHP-GIGYF-DDX6 complex assembly is required for tristetraprolin-mediated repression of an AU-rich mRNA. reference_section_type: RESULTS - id: PMID:32296183 title: A reference map of the human binary protein interactome. findings: [] - 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 YAML; directly studies human GIGYF1/2-4EHP complexes mediating translation-coupled mRNA decay and repression. GOA anchors this PMID to GO:1990261 (sequence-specific mRNA binding for translational repression, NAS), supporting the core function." findings: - statement: 4EHP-GIGYF1/2 complexes trigger co-translational mRNA decay; cells lacking them accumulate ribosome-paused transcripts, and the complex requires its interactions with the cap, DDX6 and ZNF598 to reduce mRNA levels. reference_section_type: ABSTRACT - id: PMID:33961781 title: Dual proteome-scale networks reveal cell-specific remodeling of the human interactome. findings: [] - id: PMID:36950384 title: Protein interaction studies in human induced neurons indicate convergent biology underlying autism spectrum disorders. findings: [] - id: PMID:38225382 title: Systematic discovery of protein interaction interfaces using AlphaFold and experimental validation. findings: [] - id: PMID:39251607 title: Systematic identification of post-transcriptional regulatory modules. findings: [] - id: file:human/GIGYF1/GIGYF1-uniprot.txt title: UniProt entry O75420 (GGYF1_HUMAN) findings: [] - id: file:human/GIGYF1/GIGYF1-goa.tsv title: GOA annotations for GIGYF1 findings: []