GIGYF1

UniProt ID: O75420
Organism: Homo sapiens
Review Status: COMPLETE
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Gene 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 Review

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.
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.
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.

Core Functions

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:
eukaryotic initiation factor 4E binding
Cellular Locations:
cytosol
Supporting Evidence:
  • PMID:31439631
    These proteins possess an N-terminal 4EHP-binding region (4EHP-BR) and a central compacted GYF domain

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:
eukaryotic initiation factor 4E binding
Directly Involved In:
negative regulation of translational initiation
Cellular Locations:
cytosol
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.

References

GO_REF:0000033
Annotation inferences using phylogenetic trees
PMID:20878056
Critical involvement of RQCD1 in the EGFR-Akt pathway in mammary carcinogenesis.
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.
  • 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.
PMID:32296183
A reference map of the human binary protein interactome.
PMID:33053355
4EHP and GIGYF1/2 Mediate Translation-Coupled Messenger RNA Decay.
  • 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.
PMID:33961781
Dual proteome-scale networks reveal cell-specific remodeling of the human interactome.
PMID:36950384
Protein interaction studies in human induced neurons indicate convergent biology underlying autism spectrum disorders.
PMID:38225382
Systematic discovery of protein interaction interfaces using AlphaFold and experimental validation.
PMID:39251607
Systematic identification of post-transcriptional regulatory modules.
file:human/GIGYF1/GIGYF1-uniprot.txt
UniProt entry O75420 (GGYF1_HUMAN)
file:human/GIGYF1/GIGYF1-goa.tsv
GOA annotations for GIGYF1

Suggested Questions for Experts

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?

Suggested Experiments

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.

📚 Additional Documentation

Notes

(GIGYF1-notes.md)

GIGYF1 (O75420) research notes

GRB10-interacting GYF protein 1 (PERQ1). Paralog of GIGYF2. Member of the GIGYF family.

Core function

GIGYF1 is a scaffolding/adaptor protein that nucleates 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 collision sensor E3 ligase ZNF598.

  • The 4EHP-GIGYF1/2 complex triggers co-translational mRNA decay on transcripts with
    ribosome pausing/stalling: PMID:33053355 and PMID:33053355
  • Co-translational binding of GIGYF1/2 marks transcripts with perturbed elongation for decay:
    PMID:33053355
  • GIGYF proteins have an N-terminal 4EHP-binding region and a central GYF domain that mediates
    interaction with ZNF598, TTP, or TNRC6 proteins: PMID:31439631
  • GIGYF contains a motif necessary and sufficient for direct interaction with Me31B/DDX6;
    4EHP-GIGYF-DDX6 assembly is required for TTP-mediated repression of an AU-rich mRNA:
    [PMID:31439631 "we report that GIGYF contains a motif necessary and sufficient for direct interaction with Me31B/DDX6" ; "4EHP-GIGYF-DDX6 complex assembly is required for tristetraprolin-mediated down-regulation of an AU-rich mRNA"]
  • DDX6 interaction confirmed for GIGYF1 with mutagenesis of W294/F306/F312 abolishing it
    (UniProt, PMID:31439631).

IGF/GRB10 signaling (legacy function)

Originally identified via GRB10 as a modulator of IGF-I receptor signaling
PMID:12771153. UniProt FUNCTION: "May act
cooperatively with GRB10 to regulate tyrosine kinase receptor signaling. May increase IGF1
receptor phosphorylation". This is the basis of the IBA GO:0048009 (IGF receptor signaling)
annotation. It is a real but secondary/less-characterized role relative to the translational
repression module.

ComplexPortal

  • CPX-2336: 4EHP-GIGYF1 co-translational mRNA decay complex, ZNF598 variant
  • CPX-2342: 4EHP-GIGYF1 co-translational mRNA decay complex, DDX6 variant
    Basis of NAS GO:1990261 (pre-mRNA catabolic process) and IDA GO:0032991 (complex).

Annotation assessment

  • GO:0045947 negative regulation of translational initiation (IBA): ACCEPT, core. 4EHP binding
    represses cap-dependent initiation.
  • GO:0005829 cytosol (IBA): ACCEPT.
  • GO:0048009 IGF receptor signaling pathway (IBA): KEEP_AS_NON_CORE — legacy GRB10/IGF role.
  • protein binding (IPI) x many: mostly interactome screens. The functionally meaningful one is
    EIF4E2/DDX6/ZNF598. PMID:31439631 (DDX6) -> capture as eIF4E2/DDX6 binding informative MF;
    others KEEP_AS_NON_CORE or MARK_AS_OVER_ANNOTATED (HT screens).
  • GO:1990261 pre-mRNA catabolic process (NAS, ComplexPortal): the complex mediates
    co-translational mRNA decay; MODIFY toward mRNA catabolic / translation-coupled decay would be
    more accurate but pre-mRNA catabolic is arguably wrong (it's mature mRNA). Keep as
    KEEP_AS_NON_CORE / note imprecision.
  • GO:0032991 protein-containing complex (IDA): uninformative top-level term -> KEEP_AS_NON_CORE.

Core MF/BP for review

  • MF: GO:0008190 eukaryotic initiation factor 4E binding (binds 4EHP/EIF4E2) — well supported.
  • BP: GO:0045947 negative regulation of translational initiation; GO:0017148 negative regulation
    of translation; co-translational mRNA decay (GO:0006515 / mRNA catabolic).

Pn Notes

(GIGYF1-pn-notes.md)

GIGYF1 PN Consistency Notes

  • Generated: 2026-06-18
  • Project: PROTEOSTASIS
  • Scope: PN consistency rereview against local AIGR review and available deep-research artifacts
  • UniProt: O75420
  • 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: 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/core annotation action counts: ACCEPT: 2; KEEP_AS_NON_CORE: 10; MODIFY: 2; NEW: 1

PN Consistency Summary

  • Consistency: Strong and mutually consistent. Deep research, notes, and review agree GIGYF1 is the cytosolic adaptor/scaffold that, via its N-terminal 4EHP-binding region and GYF domain, nucleates the 4EHP-GIGYF1-DDX6-ZNF598 module repressing cap-dependent initiation and triggering co-translational mRNA decay on ribosome-paused/stalled transcripts. Review ACCEPTs GO:0045947 (negative regulation of translational initiation, IBA) and adds GO:0008190 (eIF4E binding) as NEW core MF — both 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 captures the same RQC-coupled repression via the more specific GO:0045947 and the NEW GO:0008190 (eIF4E binding). GIGYF1's RQC role is real (PMID:33053355 — paused-transcript accumulation in KO; ZNF598 dependence), so GO:0006515 is defensible as an umbrella but is broader than the review's specific terms. Note the review (unlike GIGYF2's) does NOT carry GO:0072344 (rescue of stalled cytosolic ribosome) for GIGYF1 — a paralog asymmetry. Already captured (more specifically); GO:0006515 does not over-reach but adds nothing the review lacks functionally.
  • Evidence alignment: PN dossier lists no reference titles for GIGYF1; alignment is via the projected GO:0006515. Review's core PMIDs (33053355 translation-coupled decay; 31439631 GIGYF-4EHP-DDX6 assembly) cover exactly the RQC/repression biology the PN node encodes. No divergence.
  • Verdict: Fully consistent; PN RQC story already captured more precisely (GO:0045947 + NEW GO:0008190). GO:0006515 is a defensible umbrella, not an over-reach. Recommended edits: [YAML] for paralog consistency, consider whether GIGYF1 warrants GO:0072344 (rescue of stalled cytosolic ribosome) as GIGYF2's review carries it — the underlying PMID:33053355/RQC evidence is shared (curator judgment; optional).

Full Consistency Review

  • UniProt: O75420 · batch: proteostasis-batch-2026-06-07c · review status: COMPLETE
  • PN placement: Translation|Cytosolic translation|Ribosome-associated QC|other RQC processes ; PN-node mapping: RQC type=no_mapping; RQC group=mapped→GO:0006515; class/branch context_only (GO:0002181/GO:0006412 too_broad).
  • Consistency: Strong and mutually consistent. Deep research, notes, and review agree GIGYF1 is the cytosolic adaptor/scaffold that, via its N-terminal 4EHP-binding region and GYF domain, nucleates the 4EHP-GIGYF1-DDX6-ZNF598 module repressing cap-dependent initiation and triggering co-translational mRNA decay on ribosome-paused/stalled transcripts. Review ACCEPTs GO:0045947 (negative regulation of translational initiation, IBA) and adds GO:0008190 (eIF4E binding) as NEW core MF — both 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 captures the same RQC-coupled repression via the more specific GO:0045947 and the NEW GO:0008190 (eIF4E binding). GIGYF1's RQC role is real (PMID:33053355 — paused-transcript accumulation in KO; ZNF598 dependence), so GO:0006515 is defensible as an umbrella but is broader than the review's specific terms. Note the review (unlike GIGYF2's) does NOT carry GO:0072344 (rescue of stalled cytosolic ribosome) for GIGYF1 — a paralog asymmetry. Already captured (more specifically); GO:0006515 does not over-reach but adds nothing the review lacks functionally.
  • Mapping strategy: RQC group→GO:0006515 is acceptable as a broad umbrella over the review's GO:0045947/GO:0017148. No mapping change required. The class/branch context_only demotions (too_broad) are correct. Worth noting for paralog consistency: GIGYF2's review additionally carries GO:0072344; GIGYF1's does not — if PN treats the paralogs as one RQC module, the GIGYF1 review could parallel GIGYF2.
  • Evidence alignment: PN dossier lists no reference titles for GIGYF1; alignment is via the projected GO:0006515. Review's core PMIDs (33053355 translation-coupled decay; 31439631 GIGYF-4EHP-DDX6 assembly) cover exactly the RQC/repression biology the PN node encodes. No divergence.
  • Verdict: Fully consistent; PN RQC story already captured more precisely (GO:0045947 + NEW GO:0008190). GO:0006515 is a defensible umbrella, not an over-reach. Recommended edits: [YAML] for paralog consistency, consider whether GIGYF1 warrants GO:0072344 (rescue of stalled cytosolic ribosome) as GIGYF2's review carries it — the underlying PMID:33053355/RQC evidence is shared (curator judgment; optional).

PN Dossier Context

  • review_batch: proteostasis-batch-2026-06-07c
  • review_yaml: genes/human/GIGYF1/GIGYF1-ai-review.yaml
  • PN workbook rows: 1

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

  • UniProt: O75420
  • 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.

📄 View Raw YAML

 
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: []