{"gene":"GIGYF2","run_date":"2026-06-10T01:55:21","timeline":{"discoveries":[{"year":2012,"finding":"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.","method":"Co-immunoprecipitation, mouse knockout/genetic disruption, in vivo translation assays","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP, genetic disruption with defined phenotype (perinatal lethality), multiple orthogonal methods, replicated in subsequent studies","pmids":["22751931"],"is_preprint":false},{"year":2020,"finding":"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.","method":"CRISPR-Cas9 genetic screen, model substrate assays, growth-based assays","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — genome-wide CRISPR screen plus functional model substrate validation, multiple orthogonal methods, single rigorous study","pmids":["32726578"],"is_preprint":false},{"year":2016,"finding":"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.","method":"Immunoprecipitation, in vitro pull-down assays, mutational analysis of TTP tetraproline motifs, luciferase reporter assays, 4EHP knockout MEFs","journal":"RNA (New York, N.Y.)","confidence":"High","confidence_rationale":"Tier 2 / Strong — direct pulldown with mutagenesis, reporter assays, and genetic knockout with defined target mRNA phenotype","pmids":["26763119"],"is_preprint":false},{"year":2018,"finding":"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.","method":"Tethering reporter assay, domain deletion analysis, Co-immunoprecipitation with CCR4/NOT components, identification of endogenous mRNA targets","journal":"Nucleic acids research","confidence":"High","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods (tethering, Co-IP, RBP target identification), single lab, mechanistically detailed","pmids":["29554310"],"is_preprint":false},{"year":2016,"finding":"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.","method":"Co-immunoprecipitation with AGO2, tethering reporter assay (mRNA destabilization and translation repression readouts)","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — Co-IP and functional reporter assay, single lab, two orthogonal methods but limited mechanistic depth","pmids":["27157137"],"is_preprint":false},{"year":2010,"finding":"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.","method":"Crystal structure determination, SILAC/MS interactome, PRS site inhibition, subcellular localization by imaging","journal":"Structure (London, England : 1993)","confidence":"High","confidence_rationale":"Tier 1 / Moderate — crystal structure with functional validation (mutagenesis of binding site, SILAC/MS), multiple orthogonal methods in one study","pmids":["20696395"],"is_preprint":false},{"year":2009,"finding":"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.","method":"Mouse gene knockout, receptor tyrosine phosphorylation assays, ERK1/2 phosphorylation assays in primary fibroblasts, histopathology","journal":"Human molecular genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic knockout with defined signaling readouts, single lab, multiple orthogonal methods","pmids":["19744960"],"is_preprint":false},{"year":2010,"finding":"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.","method":"Immunofluorescence and subcellular fractionation, IGF-1 receptor trafficking assay, ERK1/2 and AKT phosphorylation assays upon GIGYF2 overexpression","journal":"Journal of neurochemistry","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — localization by immunofluorescence/fractionation with functional signaling readout, single lab, two orthogonal methods","pmids":["20670374"],"is_preprint":false},{"year":2022,"finding":"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.","method":"In vitro interaction assays, reporter-based translation repression assays","journal":"iScience","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vitro interaction assay plus functional reporter assay, single lab, two methods","pmids":["35756894"],"is_preprint":false},{"year":2025,"finding":"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.","method":"Interactome analysis in virus-infected cells, GIGYF2/ZNF598 depletion with viral replication readout, fCLIP-seq (formaldehyde crosslinking and immunoprecipitation sequencing), protein expression assays","journal":"Nucleic acids research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods (interactome, genetic depletion phenocopy, fCLIP-seq), single lab","pmids":["40705924"],"is_preprint":false},{"year":2025,"finding":"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.","method":"Co-immunoprecipitation, proximity ligation assay, sequence analysis of GRB10 for PPGΦ motif","journal":"Life science alliance","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — two orthogonal assays (Co-IP and PLA) with mechanistic sequence explanation, single lab; this is a negative result","pmids":["40523800"],"is_preprint":false},{"year":2023,"finding":"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.","method":"RNA immunoprecipitation (RIP), gene silencing and overexpression, mTOR pathway activity assays, endothelial-specific Gigyf2 conditional knockout mice, immunofluorescence for mTORC1 lysosomal translocation","journal":"Redox biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — RIP for RBP-mRNA binding, conditional KO mice with vascular phenotype, multiple orthogonal methods, single lab","pmids":["37517320"],"is_preprint":false},{"year":2024,"finding":"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.","method":"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","journal":"Molecular medicine (Cambridge, Mass.)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — RIP, genetic manipulation with defined signaling readout, in vivo mouse model, single lab","pmids":["39138413"],"is_preprint":false},{"year":2025,"finding":"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.","method":"Genetic depletion of 4EHP with target mRNA repression readout, co-immunoprecipitation/interaction assays","journal":"bioRxiv","confidence":"Low","confidence_rationale":"Tier 3 / Weak — preprint, single lab, interaction inferred from functional depletion readout without direct GIGYF2-specific binding assay described in abstract","pmids":[],"is_preprint":true}],"current_model":"GIGYF2 is a translational repressor that forms a complex with the cap-binding protein 4EHP to inhibit translation initiation on specific mRNAs—including during ribosome-associated quality control of faulty mRNAs—and also independently recruits the CCR4/NOT deadenylase complex to silence endogenous mRNA targets; it is additionally an RNA-binding protein that stabilizes select mRNAs (e.g., STAU1), interacts with AGO2 and the miRNA silencing machinery, and is exploited by SARS-CoV-2 Nsp2 to support viral protein production, while notably lacking a functional interaction with GRB10 in human cells despite its original identification as a GRB10-interacting protein."},"narrative":{"mechanistic_narrative":"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].","teleology":[{"year":2009,"claim":"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","pmids":["19744960"],"confidence":"Medium","gaps":["Does not establish a molecular mechanism linking GIGYF2 to receptor signaling","Connection between signaling defect and neurodegeneration not resolved"]},{"year":2010,"claim":"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","pmids":["20696395","20670374"],"confidence":"High","gaps":["Structural work used the yeast ortholog Smy2 rather than human GIGYF2","Functional consequence of ER/Golgi and stress-granule localization not mechanistically resolved"]},{"year":2012,"claim":"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","pmids":["22751931"],"confidence":"High","gaps":["Identity of the repressed mRNA subset not fully defined","Mechanism of recruitment to specific transcripts not yet established"]},{"year":2016,"claim":"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","pmids":["26763119","27157137"],"confidence":"Medium","gaps":["AGO2 association shown by co-IP without reciprocal or direct-binding validation","Full repertoire of proline-motif adaptors recruiting GIGYF2 unknown"]},{"year":2018,"claim":"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","pmids":["29554310"],"confidence":"High","gaps":["RNA sequence/structure determinants of GIGYF2 direct binding not defined","Relative contribution of each repressive domain in vivo unclear"]},{"year":2020,"claim":"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","pmids":["32726578"],"confidence":"High","gaps":["Signal coupling stalled ribosomes to GIGYF2 recruitment not fully mapped","Endogenous substrate scope of this pathway not enumerated"]},{"year":2023,"claim":"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","pmids":["37517320"],"confidence":"Medium","gaps":["How the same protein both represses and stabilizes distinct mRNAs is unresolved","Direct GIGYF2 binding site on STAU1 mRNA not mapped"]},{"year":2024,"claim":"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","pmids":["39138413"],"confidence":"Medium","gaps":["Mechanism distinguishing repressive vs stabilizing GIGYF2 activity on different targets unknown","Single-lab pathway in one tissue context"]},{"year":2025,"claim":"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","pmids":["40705924","35756894"],"confidence":"Medium","gaps":["Mechanism converting GIGYF2 from repressor to enhancer of viral protein output not defined","Role of ZNF598 cofactor in the viral context not mechanistically resolved"]},{"year":2025,"claim":"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","pmids":["40523800"],"confidence":"Medium","gaps":["Negative result; does not identify the actual mediator of GIGYF2-linked human disease","Possible context-specific or transient interactions not excluded"]},{"year":null,"claim":"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.","evidence":"","pmids":[],"confidence":"Low","gaps":["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":{"molecular_activity":[{"term_id":"GO:0003723","term_label":"RNA binding","supporting_discovery_ids":[3,11,12]},{"term_id":"GO:0045182","term_label":"translation regulator activity","supporting_discovery_ids":[0,1,3]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[2,3,5]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[0,3]}],"localization":[{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[8]},{"term_id":"GO:0005783","term_label":"endoplasmic reticulum","supporting_discovery_ids":[5]},{"term_id":"GO:0005794","term_label":"Golgi apparatus","supporting_discovery_ids":[5]},{"term_id":"GO:0005768","term_label":"endosome","supporting_discovery_ids":[7]}],"pathway":[{"term_id":"R-HSA-8953854","term_label":"Metabolism of RNA","supporting_discovery_ids":[0,1,3]},{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[0,1]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[8,9]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[6,7,11,12]}],"complexes":["GIGYF2-4EHP translational repressor complex","CCR4/NOT complex (recruited)","miRNA-induced silencing complex (RISC)"],"partners":["EIF4E2","ZFP36","CNOT1","AGO2","ZNF598","STAU1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q6Y7W6","full_name":"GRB10-interacting GYF protein 2","aliases":["PERQ amino acid-rich with GYF domain-containing protein 2","Trinucleotide repeat-containing gene 15 protein"],"length_aa":1299,"mass_kda":150.1,"function":"Key component of the 4EHP-GYF2 complex, a multiprotein complex that acts as a repressor of translation initiation (PubMed:22751931, PubMed:31439631, PubMed:35878012). In the 4EHP-GYF2 complex, acts as a factor that bridges EIF4E2 to ZFP36/TTP, linking translation repression with mRNA decay (PubMed:31439631). Also recruits and bridges the association of the 4EHP complex with the decapping effector protein DDX6, which is required for the ZFP36/TTP-mediated down-regulation of AU-rich mRNA (PubMed:31439631). May act cooperatively with GRB10 to regulate tyrosine kinase receptor signaling, including IGF1 and insulin receptors (PubMed:12771153). In association with EIF4E2, assists ribosome-associated quality control (RQC) by sequestering the mRNA cap, blocking ribosome initiation and decreasing the translational load on problematic messages. Part of a pathway that works in parallel to RQC-mediated degradation of the stalled nascent polypeptide (PubMed:32726578). GIGYF2 and EIF4E2 work downstream and independently of ZNF598, which seems to work as a scaffold that can recruit them to faulty mRNA even if alternative recruitment mechanisms may exist (PubMed:32726578) (Microbial infection) Upon SARS coronavirus-2/SARS-CoV-2 infection, the interaction with non-structural protein 2 (nsp2) enhances GIGYF2 binding to EIF4E2 and increases repression of translation initiation of genes involved in antiviral innate immune response such as IFNB1","subcellular_location":"","url":"https://www.uniprot.org/uniprotkb/Q6Y7W6/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/GIGYF2","classification":"Not Classified","n_dependent_lines":139,"n_total_lines":1208,"dependency_fraction":0.11506622516556292},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"DDOST","stoichiometry":0.2},{"gene":"MIF","stoichiometry":0.2},{"gene":"OST4","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/GIGYF2","total_profiled":1310},"omim":[{"mim_id":"617508","title":"ZINC FINGER PROTEIN 598; ZNF598","url":"https://www.omim.org/entry/617508"},{"mim_id":"612003","title":"GRB10-INTERACTING GYF PROTEIN 2; GIGYF2","url":"https://www.omim.org/entry/612003"},{"mim_id":"607688","title":"PARKINSON DISEASE 11, AUTOSOMAL DOMINANT, SUSCEPTIBILITY TO; PARK11","url":"https://www.omim.org/entry/607688"},{"mim_id":"605895","title":"EUKARYOTIC TRANSLATION INITIATION FACTOR 4E FAMILY, MEMBER 2; EIF4E2","url":"https://www.omim.org/entry/605895"},{"mim_id":"168600","title":"PARKINSON DISEASE, LATE-ONSET; PD","url":"https://www.omim.org/entry/168600"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Enhanced","locations":[{"location":"Cytosol","reliability":"Enhanced"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/GIGYF2"},"hgnc":{"alias_symbol":["KIAA0642","GYF2"],"prev_symbol":["PERQ2","PERQ3","TNRC15","PARK11"]},"alphafold":{"accession":"Q6Y7W6","domains":[{"cath_id":"3.30.1490.40","chopping":"531-600","consensus_level":"medium","plddt":86.5937,"start":531,"end":600},{"cath_id":"1.20.5","chopping":"735-912","consensus_level":"medium","plddt":83.7196,"start":735,"end":912}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q6Y7W6","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q6Y7W6-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q6Y7W6-F1-predicted_aligned_error_v6.png","plddt_mean":56.41},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=GIGYF2","jax_strain_url":"https://www.jax.org/strain/search?query=GIGYF2"},"sequence":{"accession":"Q6Y7W6","fasta_url":"https://rest.uniprot.org/uniprotkb/Q6Y7W6.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q6Y7W6/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q6Y7W6"}},"corpus_meta":[{"pmid":"22751931","id":"PMC_22751931","title":"A novel 4EHP-GIGYF2 translational repressor complex is essential for mammalian development.","date":"2012","source":"Molecular and cellular biology","url":"https://pubmed.ncbi.nlm.nih.gov/22751931","citation_count":151,"is_preprint":false},{"pmid":"32726578","id":"PMC_32726578","title":"GIGYF2 and 4EHP Inhibit Translation Initiation of Defective Messenger RNAs to Assist Ribosome-Associated Quality Control.","date":"2020","source":"Molecular cell","url":"https://pubmed.ncbi.nlm.nih.gov/32726578","citation_count":125,"is_preprint":false},{"pmid":"18358451","id":"PMC_18358451","title":"Mutations in the GIGYF2 (TNRC15) gene at the PARK11 locus in familial Parkinson disease.","date":"2008","source":"American journal of human genetics","url":"https://pubmed.ncbi.nlm.nih.gov/18358451","citation_count":122,"is_preprint":false},{"pmid":"26763119","id":"PMC_26763119","title":"Recruitment of the 4EHP-GYF2 cap-binding complex to tetraproline motifs of tristetraprolin promotes repression and degradation of mRNAs with AU-rich elements.","date":"2016","source":"RNA (New York, N.Y.)","url":"https://pubmed.ncbi.nlm.nih.gov/26763119","citation_count":63,"is_preprint":false},{"pmid":"19744960","id":"PMC_19744960","title":"GIGYF2 gene disruption in mice results in neurodegeneration and altered insulin-like growth factor signaling.","date":"2009","source":"Human molecular genetics","url":"https://pubmed.ncbi.nlm.nih.gov/19744960","citation_count":60,"is_preprint":false},{"pmid":"29554310","id":"PMC_29554310","title":"4EHP-independent repression of endogenous mRNAs by the RNA-binding protein GIGYF2.","date":"2018","source":"Nucleic acids research","url":"https://pubmed.ncbi.nlm.nih.gov/29554310","citation_count":44,"is_preprint":false},{"pmid":"20696395","id":"PMC_20696395","title":"Conserved beta-hairpin recognition by the GYF domains of Smy2 and GIGYF2 in mRNA surveillance and vesicular transport complexes.","date":"2010","source":"Structure (London, England : 1993)","url":"https://pubmed.ncbi.nlm.nih.gov/20696395","citation_count":35,"is_preprint":false},{"pmid":"19279319","id":"PMC_19279319","title":"Variation in GIGYF2 is not associated with Parkinson disease.","date":"2009","source":"Neurology","url":"https://pubmed.ncbi.nlm.nih.gov/19279319","citation_count":35,"is_preprint":false},{"pmid":"19250854","id":"PMC_19250854","title":"PARK11 gene (GIGYF2) variants Asn56Ser and Asn457Thr are not pathogenic for Parkinson's disease.","date":"2009","source":"Parkinsonism & related disorders","url":"https://pubmed.ncbi.nlm.nih.gov/19250854","citation_count":28,"is_preprint":false},{"pmid":"26152800","id":"PMC_26152800","title":"The contribution of GIGYF2 to Parkinson's disease: a meta-analysis.","date":"2015","source":"Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical 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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.\",\n      \"method\": \"Co-immunoprecipitation, mouse knockout/genetic disruption, in vivo translation assays\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP, genetic disruption with defined phenotype (perinatal lethality), multiple orthogonal methods, replicated in subsequent studies\",\n      \"pmids\": [\"22751931\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"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.\",\n      \"method\": \"CRISPR-Cas9 genetic screen, model substrate assays, growth-based assays\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genome-wide CRISPR screen plus functional model substrate validation, multiple orthogonal methods, single rigorous study\",\n      \"pmids\": [\"32726578\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"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.\",\n      \"method\": \"Immunoprecipitation, in vitro pull-down assays, mutational analysis of TTP tetraproline motifs, luciferase reporter assays, 4EHP knockout MEFs\",\n      \"journal\": \"RNA (New York, N.Y.)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — direct pulldown with mutagenesis, reporter assays, and genetic knockout with defined target mRNA phenotype\",\n      \"pmids\": [\"26763119\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"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.\",\n      \"method\": \"Tethering reporter assay, domain deletion analysis, Co-immunoprecipitation with CCR4/NOT components, identification of endogenous mRNA targets\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods (tethering, Co-IP, RBP target identification), single lab, mechanistically detailed\",\n      \"pmids\": [\"29554310\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"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.\",\n      \"method\": \"Co-immunoprecipitation with AGO2, tethering reporter assay (mRNA destabilization and translation repression readouts)\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — Co-IP and functional reporter assay, single lab, two orthogonal methods but limited mechanistic depth\",\n      \"pmids\": [\"27157137\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"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.\",\n      \"method\": \"Crystal structure determination, SILAC/MS interactome, PRS site inhibition, subcellular localization by imaging\",\n      \"journal\": \"Structure (London, England : 1993)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — crystal structure with functional validation (mutagenesis of binding site, SILAC/MS), multiple orthogonal methods in one study\",\n      \"pmids\": [\"20696395\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"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.\",\n      \"method\": \"Mouse gene knockout, receptor tyrosine phosphorylation assays, ERK1/2 phosphorylation assays in primary fibroblasts, histopathology\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic knockout with defined signaling readouts, single lab, multiple orthogonal methods\",\n      \"pmids\": [\"19744960\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"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.\",\n      \"method\": \"Immunofluorescence and subcellular fractionation, IGF-1 receptor trafficking assay, ERK1/2 and AKT phosphorylation assays upon GIGYF2 overexpression\",\n      \"journal\": \"Journal of neurochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — localization by immunofluorescence/fractionation with functional signaling readout, single lab, two orthogonal methods\",\n      \"pmids\": [\"20670374\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"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.\",\n      \"method\": \"In vitro interaction assays, reporter-based translation repression assays\",\n      \"journal\": \"iScience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vitro interaction assay plus functional reporter assay, single lab, two methods\",\n      \"pmids\": [\"35756894\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"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.\",\n      \"method\": \"Interactome analysis in virus-infected cells, GIGYF2/ZNF598 depletion with viral replication readout, fCLIP-seq (formaldehyde crosslinking and immunoprecipitation sequencing), protein expression assays\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods (interactome, genetic depletion phenocopy, fCLIP-seq), single lab\",\n      \"pmids\": [\"40705924\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"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.\",\n      \"method\": \"Co-immunoprecipitation, proximity ligation assay, sequence analysis of GRB10 for PPGΦ motif\",\n      \"journal\": \"Life science alliance\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — two orthogonal assays (Co-IP and PLA) with mechanistic sequence explanation, single lab; this is a negative result\",\n      \"pmids\": [\"40523800\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"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.\",\n      \"method\": \"RNA immunoprecipitation (RIP), gene silencing and overexpression, mTOR pathway activity assays, endothelial-specific Gigyf2 conditional knockout mice, immunofluorescence for mTORC1 lysosomal translocation\",\n      \"journal\": \"Redox biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — RIP for RBP-mRNA binding, conditional KO mice with vascular phenotype, multiple orthogonal methods, single lab\",\n      \"pmids\": [\"37517320\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"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.\",\n      \"method\": \"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\",\n      \"journal\": \"Molecular medicine (Cambridge, Mass.)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — RIP, genetic manipulation with defined signaling readout, in vivo mouse model, single lab\",\n      \"pmids\": [\"39138413\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"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.\",\n      \"method\": \"Genetic depletion of 4EHP with target mRNA repression readout, co-immunoprecipitation/interaction assays\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — preprint, single lab, interaction inferred from functional depletion readout without direct GIGYF2-specific binding assay described in abstract\",\n      \"pmids\": [],\n      \"is_preprint\": true\n    }\n  ],\n  \"current_model\": \"GIGYF2 is a translational repressor that forms a complex with the cap-binding protein 4EHP to inhibit translation initiation on specific mRNAs—including during ribosome-associated quality control of faulty mRNAs—and also independently recruits the CCR4/NOT deadenylase complex to silence endogenous mRNA targets; it is additionally an RNA-binding protein that stabilizes select mRNAs (e.g., STAU1), interacts with AGO2 and the miRNA silencing machinery, and is exploited by SARS-CoV-2 Nsp2 to support viral protein production, while notably lacking a functional interaction with GRB10 in human cells despite its original identification as a GRB10-interacting protein.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"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 [#0, #3]. 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 [#0]. 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 [#2, #5]. 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 [#3]. 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 [#1]. 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 [#11, #12]. 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 [#8, #9]. 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 [#10].\"\n  ,\n  \"teleology\": [\n    {\n      \"year\": 2009,\n      \"claim\": \"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.\",\n      \"evidence\": \"Mouse gene knockout with IGF-I receptor and ERK1/2 phosphorylation assays and histopathology\",\n      \"pmids\": [\"19744960\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Does not establish a molecular mechanism linking GIGYF2 to receptor signaling\", \"Connection between signaling defect and neurodegeneration not resolved\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"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.\",\n      \"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\",\n      \"pmids\": [\"20696395\", \"20670374\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural work used the yeast ortholog Smy2 rather than human GIGYF2\", \"Functional consequence of ER/Golgi and stress-granule localization not mechanistically resolved\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"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.\",\n      \"evidence\": \"Reciprocal co-immunoprecipitation, mouse knockout/genetic disruption, and in vivo translation assays\",\n      \"pmids\": [\"22751931\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Identity of the repressed mRNA subset not fully defined\", \"Mechanism of recruitment to specific transcripts not yet established\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"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.\",\n      \"evidence\": \"In vitro pull-downs with TTP tetraproline mutagenesis, luciferase reporters, 4EHP knockout MEFs, plus AGO2 co-IP and tethering reporter assays\",\n      \"pmids\": [\"26763119\", \"27157137\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"AGO2 association shown by co-IP without reciprocal or direct-binding validation\", \"Full repertoire of proline-motif adaptors recruiting GIGYF2 unknown\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"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.\",\n      \"evidence\": \"Tethering reporter assays, domain deletion mapping, co-IP with CCR4/NOT components, and identification of endogenous mRNA targets\",\n      \"pmids\": [\"29554310\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"RNA sequence/structure determinants of GIGYF2 direct binding not defined\", \"Relative contribution of each repressive domain in vivo unclear\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"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.\",\n      \"evidence\": \"Genome-wide CRISPR-Cas9 screen with model substrate and growth-based assays\",\n      \"pmids\": [\"32726578\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Signal coupling stalled ribosomes to GIGYF2 recruitment not fully mapped\", \"Endogenous substrate scope of this pathway not enumerated\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"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.\",\n      \"evidence\": \"RNA immunoprecipitation, gene silencing/overexpression, mTOR activity assays, and endothelial-specific conditional knockout mice\",\n      \"pmids\": [\"37517320\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"How the same protein both represses and stabilizes distinct mRNAs is unresolved\", \"Direct GIGYF2 binding site on STAU1 mRNA not mapped\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"The stabilizing function was extended to metabolic disease by showing GIGYF2-STAU1-PTEN regulation drives hepatic insulin resistance, broadening its physiological reach.\",\n      \"evidence\": \"RIP for GIGYF2-mRNA binding, hepatocyte silencing/overexpression, PI3K/AKT/PTEN western blotting, and high-fat-diet mouse insulin-resistance model\",\n      \"pmids\": [\"39138413\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism distinguishing repressive vs stabilizing GIGYF2 activity on different targets unknown\", \"Single-lab pathway in one tissue context\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"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.\",\n      \"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\",\n      \"pmids\": [\"40705924\", \"35756894\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism converting GIGYF2 from repressor to enhancer of viral protein output not defined\", \"Role of ZNF598 cofactor in the viral context not mechanistically resolved\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"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.\",\n      \"evidence\": \"Co-immunoprecipitation, proximity ligation assay, and sequence analysis of GRB10 for the GYF-binding PPGΦ motif\",\n      \"pmids\": [\"40523800\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Negative result; does not identify the actual mediator of GIGYF2-linked human disease\", \"Possible context-specific or transient interactions not excluded\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"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.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"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\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0003723\", \"supporting_discovery_ids\": [3, 11, 12]},\n      {\"term_id\": \"GO:0045182\", \"supporting_discovery_ids\": [0, 1, 3]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [2, 3, 5]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [0, 3]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [8]},\n      {\"term_id\": \"GO:0005783\", \"supporting_discovery_ids\": [5]},\n      {\"term_id\": \"GO:0005794\", \"supporting_discovery_ids\": [5]},\n      {\"term_id\": \"GO:0005768\", \"supporting_discovery_ids\": [7]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-8953854\", \"supporting_discovery_ids\": [0, 1, 3]},\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [0, 1]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [8, 9]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [6, 7, 11, 12]}\n    ],\n    \"complexes\": [\"GIGYF2-4EHP translational repressor complex\", \"CCR4/NOT complex (recruited)\", \"miRNA-induced silencing complex (RISC)\"],\n    \"partners\": [\"EIF4E2\", \"ZFP36\", \"CNOT1\", \"AGO2\", \"ZNF598\", \"STAU1\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":8,"faith_total":8,"faith_pct":100.0}}