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.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0045947 negative regulation of translational initiation | IBA GO_REF:0000033 | ACCEPT | 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. 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. Supporting Evidence: PMID:33053355 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. PMID:31439631 These proteins possess an N-terminal 4EHP-binding region (4EHP-BR) and a central compacted GYF domain |
| GO:0005829 cytosol | IBA GO_REF:0000033 | ACCEPT | 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. Reason: Cytosolic activity is expected for a translation/mRNA-decay adaptor and is phylogenetically well supported; the complex acts co-translationally on cytoplasmic mRNAs. Supporting Evidence: PMID:33053355 co-translational binding of GIGYF1/2 to the mRNA marks transcripts with perturbed elongation to decay. |
| GO:0048009 insulin-like growth factor receptor signaling pathway | IBA GO_REF:0000033 | KEEP AS NON CORE | 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. 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. Supporting Evidence: file:human/GIGYF1/GIGYF1-uniprot.txt May increase IGF1 receptor phosphorylation under |
| 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 an interaction dataset. Records a real interaction but the term is uninformative about function. Reason: Bare protein binding does not capture GIGYF1's molecular function; the informative interaction (eIF4E2/EIF4E2) is captured separately as a core MF. Supporting Evidence: file:human/GIGYF1/GIGYF1-goa.tsv PMID:28698298 |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | KEEP AS NON CORE | Summary: Generic protein-binding annotation derived from a large-scale binary interactome map (HuRI). Uninformative as a molecular function. 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. Supporting Evidence: PMID:32296183 A reference map of the human binary protein interactome. |
| GO:0005515 protein binding | IPI PMID:33053355 4EHP and GIGYF1/2 Mediate Translation-Coupled Messenger RNA ... | KEEP AS NON CORE | 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. 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. Supporting Evidence: PMID:33053355 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. |
| GO:0005515 protein binding | IPI PMID:33961781 Dual proteome-scale networks reveal cell-specific remodeling... | KEEP AS NON CORE | Summary: Generic protein-binding annotation from the BioPlex affinity-purification interactome. Records interactions including DDX6 but the term is uninformative. 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. Supporting Evidence: PMID:33961781 Dual proteome-scale networks reveal cell-specific remodeling of the human interactome. |
| GO:0005515 protein binding | IPI PMID:36950384 Protein interaction studies in human induced neurons indicat... | KEEP AS NON CORE | 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. Reason: High-throughput interactome dataset; provides no specific functional insight for GIGYF1 beyond a network membership. Supporting Evidence: PMID:36950384 Protein interaction studies in human induced neurons indicate convergent biology underlying autism spectrum disorders. |
| GO:0005515 protein binding | IPI PMID:38225382 Systematic discovery of protein interaction interfaces using... | KEEP AS NON CORE | Summary: Generic protein-binding annotation from an AlphaFold-based interface prediction/validation study. Uninformative as a molecular function. Reason: Computational interface discovery dataset; not a specific functional characterization of GIGYF1. Supporting Evidence: PMID:38225382 Systematic discovery of protein interaction interfaces using AlphaFold and experimental validation. |
| GO:0005515 protein binding | IPI PMID:39251607 Systematic identification of post-transcriptional regulatory... | KEEP AS NON CORE | Summary: Generic protein-binding annotation from a systematic post-transcriptional regulatory-module study. Uninformative as a molecular function. Reason: Records a real interaction (DDX6) consistent with the repression module but the generic term is not elevated to core. Supporting Evidence: PMID:39251607 Systematic identification of post-transcriptional regulatory modules. |
| GO:1990261 pre-mRNA catabolic process | NAS PMID:33053355 4EHP and GIGYF1/2 Mediate Translation-Coupled Messenger RNA ... | MODIFY | 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. 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 replacements: nuclear-transcribed mRNA catabolic process Supporting Evidence: PMID:33053355 Here, we show that 4EHP-GIGYF1/2 complexes trigger co-translational mRNA decay. Human cells lacking these proteins accumulate mRNAs with prominent ribosome pausing. |
| GO:0005515 protein binding | IPI PMID:31439631 Molecular basis for GIGYF-Me31B complex assembly in 4EHP-med... | MODIFY | 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. 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 replacements: negative regulation of translation Supporting Evidence: PMID:31439631 we report that GIGYF contains a motif necessary and sufficient for direct interaction with Me31B/DDX6 |
| 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 a study of RQCD1 (CNOT9) in the EGFR-Akt pathway, in which GIGYF1 was identified in associated complexes. Uninformative as a molecular function. Reason: Records interactions (EGFR/AKT/GRB10/RQCD1 network) consistent with the legacy receptor-signaling role but the generic term is not elevated. Supporting Evidence: PMID:20878056 Critical involvement of RQCD1 in the EGFR-Akt pathway in mammary carcinogenesis. |
| GO:0008190 eukaryotic initiation factor 4E binding | IPI PMID:31439631 Molecular basis for GIGYF-Me31B complex assembly in 4EHP-med... | NEW | 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. 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). Supporting Evidence: PMID:31439631 These proteins possess an N-terminal 4EHP-binding region (4EHP-BR) and a central compacted GYF domain file:human/GIGYF1/GIGYF1-uniprot.txt O75420; O60573-1: EIF4E2; NbExp=12; IntAct=EBI-947774, EBI-32715389; |
| GO:0032991 protein-containing complex | IDA PMID:20878056 Critical involvement of RQCD1 in the EGFR-Akt pathway in mam... | KEEP AS NON CORE | Summary: Annotation that GIGYF1 is part of a protein-containing complex. The top-level term is uninformative about which complex. 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. Supporting Evidence: PMID:20878056 Critical involvement of RQCD1 in the EGFR-Akt pathway in mammary carcinogenesis. |
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Download this section (compressed HTML)Q: Does GIGYF1 act redundantly with GIGYF2 in co-translational mRNA decay, or do the paralogs have distinct target-mRNA repertoires and tissue contexts?
Q: To what extent does GIGYF1 contribute to ZNF598-dependent ribosome-collision quality control versus 4EHP-only translational repression at uncollided mRNAs?
Experiment: Ribosome profiling and mRNA-decay measurements in GIGYF1 single-knockout versus GIGYF1/GIGYF2 double-knockout cells to define paralog-specific target mRNAs.
Experiment: 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.
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