Affinage

GIGYF2

GRB10-interacting GYF protein 2 · UniProt Q6Y7W6

Length
1299 aa
Mass
150.1 kDa
Annotated
2026-06-10
39 papers in source corpus 13 papers cited in narrative 14 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 8/8 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

GIGYF2 is a translational repressor and RNA-binding adaptor that controls the fate of specific mRNAs by coupling sequence- and quality-recognition signals to the translation and decay machinery (PMID:22751931, PMID:29554310). Its central activity is to form a stable complex with the cap-binding protein 4EHP, an interaction required to stabilize both proteins and to repress translation initiation on a subset of mRNAs; disruption of this complex de-represses translation and causes perinatal lethality in mice (PMID:22751931). GIGYF2 is recruited to target transcripts through its GYF domain, which recognizes proline-rich (PPGΦ) motifs in partner RNA-binding proteins such as tristetraprolin, thereby directing 4EHP-dependent repression and decay of AU-rich-element mRNAs (PMID:26763119, PMID:20696395). Beyond 4EHP, GIGYF2 silences endogenous mRNAs through a 4EHP-independent route by recruiting the CCR4/NOT deadenylase complex via multiple interfaces, and contains three separable repressive domains (PMID:29554310). A major dedicated function is ribosome-associated quality control: together with 4EHP, GIGYF2 forms a feedback loop that prevents re-initiation on mRNAs undergoing failed translation, limiting accumulation of toxic incomplete polypeptides (PMID:32726578). GIGYF2 also acts as an RNA-binding protein that stabilizes select transcripts including STAU1, with downstream consequences for mTORC1 and PI3K/AKT signaling in vascular and hepatic tissues (PMID:37517320, PMID:39138413). SARS-CoV-2 Nsp2 hijacks GIGYF2, associating with it and 4EHP, recruiting it to viral replication sites, and exploiting it to support production of viral proteins (PMID:35756894, PMID:40705924). Despite its original identification as a GRB10-interacting protein, human GIGYF2 does not interact with GRB10, owing to the absence of a GYF-binding PPGΦ motif in human GRB10 (PMID:40523800).

Mechanistic history

Synthesis pass · year-by-year structured walk · 10 steps
  1. 2009 Medium

    Before its molecular function was known, GIGYF2 was tied to organismal physiology by asking whether its loss alters signaling and neuronal integrity, revealing a role in modulating IGF-I receptor signaling and protecting motor neurons.

    Evidence Mouse gene knockout with IGF-I receptor and ERK1/2 phosphorylation assays and histopathology

    PMID:19744960

    Open questions at the time
    • Does not establish a molecular mechanism linking GIGYF2 to receptor signaling
    • Connection between signaling defect and neurodegeneration not resolved
  2. 2010 High

    The basis of GIGYF2 target recognition and its cellular context were defined by determining how its GYF domain engages proline-rich ligands and where the protein resides, establishing a structural mode of partner binding and dynamic localization.

    Evidence Crystal structure of the Smy2 GYF domain bound to a proline-rich sequence, SILAC/MS interactome, and subcellular imaging; complemented by endosomal localization and IGF-1 receptor trafficking assays

    PMID:20670374 PMID:20696395

    Open questions at the time
    • Structural work used the yeast ortholog Smy2 rather than human GIGYF2
    • Functional consequence of ER/Golgi and stress-granule localization not mechanistically resolved
  3. 2012 High

    The core molecular activity of GIGYF2 was established by testing its partnership with the cap-binding protein 4EHP, defining the GIGYF2-4EHP complex as a translational repressor essential for development.

    Evidence Reciprocal co-immunoprecipitation, mouse knockout/genetic disruption, and in vivo translation assays

    PMID:22751931

    Open questions at the time
    • Identity of the repressed mRNA subset not fully defined
    • Mechanism of recruitment to specific transcripts not yet established
  4. 2016 Medium

    How GIGYF2 reaches specific transcripts and integrates with the silencing machinery was addressed by showing it is recruited via TTP proline motifs and associates with AGO2, linking the complex to ARE-mediated and miRNA-mediated silencing.

    Evidence In vitro pull-downs with TTP tetraproline mutagenesis, luciferase reporters, 4EHP knockout MEFs, plus AGO2 co-IP and tethering reporter assays

    PMID:26763119 PMID:27157137

    Open questions at the time
    • AGO2 association shown by co-IP without reciprocal or direct-binding validation
    • Full repertoire of proline-motif adaptors recruiting GIGYF2 unknown
  5. 2018 High

    The repressive logic of GIGYF2 was dissected by separating its 4EHP-dependent and 4EHP-independent outputs, revealing CCR4/NOT recruitment and intrinsic RNA-binding as parallel silencing routes.

    Evidence Tethering reporter assays, domain deletion mapping, co-IP with CCR4/NOT components, and identification of endogenous mRNA targets

    PMID:29554310

    Open questions at the time
    • RNA sequence/structure determinants of GIGYF2 direct binding not defined
    • Relative contribution of each repressive domain in vivo unclear
  6. 2020 High

    A dedicated cellular surveillance function was established by asking whether GIGYF2/4EHP act in quality control, showing they form a feedback loop that blocks re-translation of faulty mRNAs to limit toxic incomplete proteins.

    Evidence Genome-wide CRISPR-Cas9 screen with model substrate and growth-based assays

    PMID:32726578

    Open questions at the time
    • Signal coupling stalled ribosomes to GIGYF2 recruitment not fully mapped
    • Endogenous substrate scope of this pathway not enumerated
  7. 2023 Medium

    An mRNA-stabilizing arm of GIGYF2 function was uncovered by testing it as an RBP for STAU1, connecting GIGYF2 to mTORC1-S6K1 activation and endothelial senescence.

    Evidence RNA immunoprecipitation, gene silencing/overexpression, mTOR activity assays, and endothelial-specific conditional knockout mice

    PMID:37517320

    Open questions at the time
    • How the same protein both represses and stabilizes distinct mRNAs is unresolved
    • Direct GIGYF2 binding site on STAU1 mRNA not mapped
  8. 2024 Medium

    The stabilizing function was extended to metabolic disease by showing GIGYF2-STAU1-PTEN regulation drives hepatic insulin resistance, broadening its physiological reach.

    Evidence RIP for GIGYF2-mRNA binding, hepatocyte silencing/overexpression, PI3K/AKT/PTEN western blotting, and high-fat-diet mouse insulin-resistance model

    PMID:39138413

    Open questions at the time
    • Mechanism distinguishing repressive vs stabilizing GIGYF2 activity on different targets unknown
    • Single-lab pathway in one tissue context
  9. 2025 Medium

    GIGYF2 was redefined as a hijacked host factor by determining that SARS-CoV-2 Nsp2 recruits it to viral replication sites and exploits it to promote viral protein production, inverting its repressive role.

    Evidence Infected-cell interactome, GIGYF2/ZNF598 depletion with viral replication phenocopy, fCLIP-seq mapping viral RNA contacts, and protein expression assays; earlier Nsp2-4EHP/GIGYF2 interaction and reporter assays

    PMID:35756894 PMID:40705924

    Open questions at the time
    • Mechanism converting GIGYF2 from repressor to enhancer of viral protein output not defined
    • Role of ZNF598 cofactor in the viral context not mechanistically resolved
  10. 2025 Medium

    A long-standing assumption was overturned by directly testing the GIGYF2-GRB10 interaction in human cells and finding it absent, excluding GRB10/insulin signaling as the route for human GIGYF2 disease phenotypes.

    Evidence Co-immunoprecipitation, proximity ligation assay, and sequence analysis of GRB10 for the GYF-binding PPGΦ motif

    PMID:40523800

    Open questions at the time
    • Negative result; does not identify the actual mediator of GIGYF2-linked human disease
    • Possible context-specific or transient interactions not excluded

Open questions

Synthesis pass · forward-looking unresolved questions
  • It remains unknown what molecular switch determines whether GIGYF2 represses, decays, or stabilizes a given mRNA, and how upstream signals (codon optimality, stalled ribosomes, adaptor occupancy) select among these opposing outcomes.
  • No unifying model reconciles repressor vs stabilizer activities
  • Codon-optimality input (ZC3H7A/B) rests on a single preprint without direct GIGYF2 binding assay
  • Transcript-level rules governing partner selection undefined

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0003723 RNA binding 3 GO:0045182 translation regulator activity 3 GO:0060090 molecular adaptor activity 3 GO:0098772 molecular function regulator activity 2
Localization
GO:0005768 endosome 1 GO:0005783 endoplasmic reticulum 1 GO:0005794 Golgi apparatus 1 GO:0005829 cytosol 1
Pathway
R-HSA-162582 Signal Transduction 4 R-HSA-8953854 Metabolism of RNA 3 R-HSA-1643685 Disease 2 R-HSA-392499 Metabolism of proteins 2
Partners
AGO2CNOT1EIF4E2STAU1ZFP36ZNF598
Complex memberships
CCR4/NOT complex (recruited)GIGYF2-4EHP translational repressor complexmiRNA-induced silencing complex (RISC)

Evidence

Reading pass · 14 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2012 GIGYF2 directly interacts with the mammalian cap-binding protein 4EHP (m4EHP), forming a translational repressor complex; this interaction is required for stabilization of both proteins. Disruption of the m4EHP-GIGYF2 complex leads to increased translation and perinatal lethality in mice, establishing the complex as a repressor of a subset of mRNAs during embryonic development. Co-immunoprecipitation, mouse knockout/genetic disruption, in vivo translation assays Molecular and cellular biology High 22751931
2020 GIGYF2 and 4EHP mediate a negative feedback loop that inhibits translation initiation on mRNAs undergoing failed translation (ribosome-associated quality control). CRISPR-Cas9 screening established that GIGYF2 and 4EHP act together to prevent additional rounds of translation of faulty mRNAs, thereby limiting accumulation of toxic incomplete polypeptides. CRISPR-Cas9 genetic screen, model substrate assays, growth-based assays Molecular cell High 32726578
2016 GIGYF2 (GYF2) is recruited to mRNAs via direct interaction with the RNA-binding protein tristetraprolin (TTP) through conserved tetraproline motifs of TTP. This interaction enables the 4EHP-GYF2 complex to repress translation and promote decay of AU-rich element-containing mRNAs. 4EHP knockout MEFs show increased induction and slower turnover of TTP-target mRNAs. Immunoprecipitation, in vitro pull-down assays, mutational analysis of TTP tetraproline motifs, luciferase reporter assays, 4EHP knockout MEFs RNA (New York, N.Y.) High 26763119
2018 GIGYF2 represses endogenous mRNAs through two distinct mechanisms: (1) a 4EHP-dependent mechanism affecting translation, and (2) a 4EHP-independent mechanism involving recruitment of the CCR4/NOT deadenylation complex through multiple interfaces. Three independent repressive domains were identified in GIGYF2 by tethering assays, and GIGYF2 was shown to be an RNA-binding protein with identifiable endogenous mRNA targets. Tethering reporter assay, domain deletion analysis, Co-immunoprecipitation with CCR4/NOT components, identification of endogenous mRNA targets Nucleic acids research High 29554310
2016 Full-length GIGYF2 co-immunoprecipitates with AGO2 in human cells, and tethered GIGYF2 exhibits strong, dose-dependent silencing activity involving both mRNA destabilization and translational repression, placing GIGYF2 as a component of the miRNA-induced silencing complex. Co-immunoprecipitation with AGO2, tethering reporter assay (mRNA destabilization and translation repression readouts) Biochemical and biophysical research communications Medium 27157137
2010 The crystal structure of the GYF domain of the GIGYF2 yeast ortholog Smy2 in complex with a proline-rich sequence (PRS) reveals that PRS recognition requires accommodation of the beta-hairpin of the PPGL motif ligand in an extended hydrophobic cleft, a specificity feature conserved in human GIGYF2. SILAC/MS experiments showed that GIGYF2 interacts with mRNA surveillance factors, vesicular transport proteins, and Atrophin-1. GIGYF2 localizes to the ER and Golgi in resting cells and redistributes to stress granules upon environmental challenge. Crystal structure determination, SILAC/MS interactome, PRS site inhibition, subcellular localization by imaging Structure (London, England : 1993) High 20696395
2009 Loss-of-function of GIGYF2 in mice causes decreased IGF-I-stimulated IGF-I receptor tyrosine phosphorylation and augmented ERK1/2 phosphorylation in primary embryo fibroblasts, establishing GIGYF2's role in modulating IGF-I signaling. Heterozygous Gigyf2+/- mice develop age-related motor dysfunction and neurodegeneration with Lewy body-like inclusions in spinal motor neurons. Mouse gene knockout, receptor tyrosine phosphorylation assays, ERK1/2 phosphorylation assays in primary fibroblasts, histopathology Human molecular genetics Medium 19744960
2010 GIGYF2 is present in endosomal compartments (Rab4-positive endosomes) in mammalian brain neurons. Overexpression of GIGYF2 alters IGF-1 receptor trafficking and enhances IGF-1-induced ERK1/2 phosphorylation but not IGF-1 receptor or AKT phosphorylation, suggesting a role for GIGYF2 in regulating signaling specificity at endosomes. Immunofluorescence and subcellular fractionation, IGF-1 receptor trafficking assay, ERK1/2 and AKT phosphorylation assays upon GIGYF2 overexpression Journal of neurochemistry Medium 20670374
2022 SARS-CoV-2 NSP2 physically associates with both 4EHP and a central segment of GIGYF2 in the cytoplasm, and functionally impairs GIGYF2-mediated translation repression as demonstrated by reporter-based assays. In vitro interaction assays, reporter-based translation repression assays iScience Medium 35756894
2025 SARS-CoV-2 Nsp2 recruits GIGYF2 to double-membrane vesicles (viral replication sites) in infected cells; depletion of GIGYF2 or its cofactor ZNF598 phenocopies viral replication defects caused by Nsp2 deletion. fCLIP-seq identified viral RNA regions (encoding M and Orf6) that interact with GIGYF2, and GIGYF2 depletion reduced protein expression of M and Orf6, establishing GIGYF2 as a host factor exploited by Nsp2 to support viral protein production. Interactome analysis in virus-infected cells, GIGYF2/ZNF598 depletion with viral replication readout, fCLIP-seq (formaldehyde crosslinking and immunoprecipitation sequencing), protein expression assays Nucleic acids research Medium 40705924
2025 Human GIGYF2 does not interact with GRB10 in human cell lines, as demonstrated by co-immunoprecipitation and proximity ligation assays. The lack of interaction is explained by the absence of the critical GYF domain-binding PPGΦ sequence in human GRB10 protein, establishing that disease phenotypes associated with GIGYF2 mutations in humans are not mediated through a GIGYF2-GRB10 complex or insulin/IGF signaling via GRB10. Co-immunoprecipitation, proximity ligation assay, sequence analysis of GRB10 for PPGΦ motif Life science alliance Medium 40523800
2023 GIGYF2 acts as an RNA-binding protein (RBP) that enhances STAU1 mRNA stability; STAU1 in turn upregulates LAMTOR4 by binding its intron region, activating mTORC1-S6K1 signaling via lysosomal recruitment of mTORC1, ultimately causing endothelial cell senescence and vascular dysfunction. RNA immunoprecipitation (RIP), gene silencing and overexpression, mTOR pathway activity assays, endothelial-specific Gigyf2 conditional knockout mice, immunofluorescence for mTORC1 lysosomal translocation Redox biology Medium 37517320
2024 GIGYF2 mediates hepatic insulin resistance by enhancing STAU1 mRNA stability (as an RBP), leading to STAU1-mediated stabilization of PTEN mRNA via its 3'UTR, which inactivates PI3K/AKT signaling. GIGYF2 knockdown in high-fat diet mice alleviates insulin resistance and restores PI3K/AKT signaling. RNA immunoprecipitation (RIP) for GIGYF2-mRNA binding, gene silencing and overexpression in hepatocytes, Western blotting for PI3K/AKT/PTEN, high-fat diet mouse IR model with glucose tolerance assay Molecular medicine (Cambridge, Mass.) Medium 39138413
2025 ZC3H7A and ZC3H7B RNA-binding proteins interact with the GIGYF2/4EHP translation repressor complex to block translation initiation of mRNAs enriched in non-optimal (A/U3) codons; depletion of 4EHP impairs repression of these mRNAs, placing GIGYF2/4EHP downstream of ZC3H7A/B in a codon optimality-sensing pathway. Genetic depletion of 4EHP with target mRNA repression readout, co-immunoprecipitation/interaction assays bioRxivpreprint Low

Source papers

Stage 0 corpus · 39 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2012 A novel 4EHP-GIGYF2 translational repressor complex is essential for mammalian development. Molecular and cellular biology 151 22751931
2020 GIGYF2 and 4EHP Inhibit Translation Initiation of Defective Messenger RNAs to Assist Ribosome-Associated Quality Control. Molecular cell 125 32726578
2008 Mutations in the GIGYF2 (TNRC15) gene at the PARK11 locus in familial Parkinson disease. American journal of human genetics 122 18358451
2016 Recruitment of the 4EHP-GYF2 cap-binding complex to tetraproline motifs of tristetraprolin promotes repression and degradation of mRNAs with AU-rich elements. RNA (New York, N.Y.) 63 26763119
2009 GIGYF2 gene disruption in mice results in neurodegeneration and altered insulin-like growth factor signaling. Human molecular genetics 60 19744960
2018 4EHP-independent repression of endogenous mRNAs by the RNA-binding protein GIGYF2. Nucleic acids research 44 29554310
2010 Conserved beta-hairpin recognition by the GYF domains of Smy2 and GIGYF2 in mRNA surveillance and vesicular transport complexes. Structure (London, England : 1993) 35 20696395
2009 Variation in GIGYF2 is not associated with Parkinson disease. Neurology 35 19279319
2009 PARK11 gene (GIGYF2) variants Asn56Ser and Asn457Thr are not pathogenic for Parkinson's disease. Parkinsonism & related disorders 28 19250854
2015 The contribution of GIGYF2 to Parkinson's disease: a meta-analysis. Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology 25 26152800
2010 GIGYF2 is present in endosomal compartments in the mammalian brains and enhances IGF-1-induced ERK1/2 activation. Journal of neurochemistry 25 20670374
2010 Mutational analysis of GIGYF2, ATP13A2 and GBA genes in Brazilian patients with early-onset Parkinson's disease. Neuroscience letters 21 20816920
2023 Aberrant hyper-expression of the RNA binding protein GIGYF2 in endothelial cells modulates vascular aging and function. Redox biology 20 37517320
2022 The SARS-CoV-2 protein NSP2 impairs the silencing capacity of the human 4EHP-GIGYF2 complex. iScience 20 35756894
2009 Non-synonymous GIGYF2 variants in Parkinson's disease from two Asian populations. Human genetics 20 19449032
2015 GIGYF2 mutation in late-onset Parkinson's disease with cognitive impairment. Journal of human genetics 19 26134514
2009 Haplotype analysis of the PARK 11 gene, GIGYF2, in sporadic Parkinson's disease. Movement disorders : official journal of the Movement Disorder Society 19 19117363
2016 Post-transcriptional gene silencing activity of human GIGYF2. Biochemical and biophysical research communications 18 27157137
2010 Mutational screening and zebrafish functional analysis of GIGYF2 as a Parkinson-disease gene. Neurobiology of aging 18 20060621
2009 GIGYF2 has no major role in Parkinson genetic etiology in a Belgian population. Neurobiology of aging 18 19321232
2009 GIGYF2 Asn56Ser and Asn457Thr mutations in Parkinson disease patients. Neuroscience letters 18 19429085
2009 GIGYF2 mutations are not a frequent cause of familial Parkinson's disease. Parkinsonism & related disorders 18 19482505
2012 Mutation analysis of LRRK2, SCNA, UCHL1, HtrA2 and GIGYF2 genes in Chinese patients with autosomal dorminant Parkinson's disease. Neuroscience letters 14 22503729
2021 Elevated GIGYF2 expression suppresses tumor migration and enhances sensitivity to temozolomide in malignant glioma. Cancer gene therapy 13 34059782
2024 RNA-binding protein GIGYF2 orchestrates hepatic insulin resistance through STAU1/PTEN-mediated disruption of the PI3K/AKT signaling cascade. Molecular medicine (Cambridge, Mass.) 12 39138413
2009 Analysis of the GIGYF2 gene in familial and sporadic Parkinson disease in the Spanish population. European journal of neurology 12 19845746
2010 Novel GIGYF2 gene variants in patients with Parkinson's disease in Chinese population. Neuroscience letters 11 20178831
2019 SETD2, GIGYF2, FGFR3, BCR, KMT2C, and TSC2 as candidate genes for differentiating multilocular cystic renal neoplasm of low malignant potential from clear cell renal cell carcinoma with cystic change. Investigative and clinical urology 10 31098421
2014 Meta-analyses of seven GIGYF2 polymorphisms with Parkinson's disease. Biomedical reports 8 25279164
2011 Follow-up study of variants of the GIGYF2 gene in Chinese patients with Parkinson’s disease. Journal of clinical neuroscience : official journal of the Neurosurgical Society of Australasia 8 22115759
2009 Follow-up study of the GIGYF2 gene in French families with Parkinson's disease. Neurobiology of aging 7 20004041
2009 The GIGYF2 variants are not associated with Parkinson's disease in the mainland Chinese population. Parkinsonism & related disorders 7 20044296
2009 GIGYF2 Asn56Ser mutation is rare in Chinese Parkinson's disease patients. Neuroscience letters 6 19638301
2010 No evidence for pathogenic role of GIGYF2 mutation in Parkinson disease in Japanese patients. Neuroscience letters 5 20641165
2009 Is GIGYF2 the defective gene at the PARK11 locus? Current neurology and neuroscience reports 3 19348706
2025 SARS-CoV-2 Nsp2 recruits GIGYF2 near viral replication sites and supports viral protein production. Nucleic acids research 1 40705924
2025 No evidence that human GIGYF2 interacts with GRB10: implications for human disease. Life science alliance 0 40523800
2025 RNA-binding protein GIGYF2 promotes colorectal cancer progression through activation of the METTL3/SERP1/STAT3 axis in an m6A-IGF2BP2-dependent manner. Biochemical pharmacology 0 41130307
2023 Identification of zebrafish GIGYF2 presents in egg/embryo as an antibacterial protein. Fish & shellfish immunology 0 37467901

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