GIGYF2 (GRB10-interacting GYF protein 2; TNRC15) is the principal scaffold of the 4EHP-GYF2 translational-repressor complex. Through an N-terminal 4EHP-binding motif it binds the non-canonical cap-binding protein 4EHP (EIF4E2), which occupies the mRNA 5' cap but cannot recruit eIF4G, thereby blocking cap-dependent translation initiation. Its central GYF domain bridges EIF4E2 to RNA-associated repressors, including the AU-rich-element protein ZFP36/tristetraprolin, the miRNA-pathway Argonaute AGO2/TNRC6 machinery, and the collided-ribosome sensor E3 ligase ZNF598, and it recruits the DEAD-box helicase/decapping effector DDX6, coupling translational repression to mRNA destabilization and decay. A major role is in ribosome-associated quality control: on mRNAs that cause ribosome stalling, GIGYF2-EIF4E2 impose a negative-feedback loop that suppresses further initiation, reducing translational load and working in parallel with degradation of the stalled nascent chain. The 4EHP-GIGYF2 complex is essential for mammalian embryonic development, and compromised GIGYF2 function causes neurodevelopmental and neuropsychiatric phenotypes; the gene lies at the PARK11 locus (Parkinson disease 11), although its causal role in Parkinson disease is unclear. GIGYF2 is predominantly cytosolic and also localizes to stress granules, P-bodies and neuronal perikarya/proximal dendrites; SARS-CoV-2 nsp2 co-opts GIGYF2 to repress interferon (IFNB1) translation. A separate legacy role, via the GRB10 adapter, modulates IGF-1/insulin receptor signaling.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0000900 mRNA regulatory element binding translation repressor activity | IBA GO_REF:0000033 | ACCEPT | Summary: Captures GIGYF2's role as a sequence-/element-directed translational repressor: it is recruited by RNA-binding adaptors (ZFP36/TTP, TNRC6/AGO2) to specific mRNA elements and represses their translation via 4EHP. Well supported and core. Reason: GIGYF2 bridges EIF4E2 to element-binding proteins (e.g. ZFP36/TTP on AU-rich elements) to repress translation of specific transcripts, consistent with this MF. Supporting Evidence: file:human/GIGYF2/GIGYF2-uniprot.txt acts as a factor that bridges EIF4E2 to ZFP36/TTP, linking PMID:27157137 upon tethering to a reporter mRNA, GIGYF2 exhibits strong, dose-dependent silencing activity, involving both mRNA destabilization and translational repression. |
| GO:0045947 negative regulation of translational initiation | IBA GO_REF:0000033 | ACCEPT | Summary: Core function: the 4EHP-GIGYF2 complex represses cap-dependent translation initiation. Strongly supported phylogenetically and experimentally. Reason: UniProt and primary literature establish the 4EHP-GYF2 complex as a repressor of translation initiation. Supporting Evidence: file:human/GIGYF2/GIGYF2-uniprot.txt Key component of the 4EHP-GYF2 complex, a multiprotein |
| GO:0016020 membrane | IBA GO_REF:0000033 | MARK AS OVER ANNOTATED | Summary: Broad 'membrane' localization, phylogenetically inferred. GIGYF2 is a cytosolic mRNA-associated protein; any membrane association is peripheral (e.g. with membrane-associated translation sites or vesicles) and not its site of action. Reason: GIGYF2 has no membrane-spanning domain; the informative localizations are cytosol, stress granules and P-bodies. The generic 'membrane' is_active_in is not supported as a functional site. Supporting Evidence: file:human/GIGYF2/GIGYF2-uniprot.txt Key component of the 4EHP-GYF2 complex, a multiprotein |
| GO:0005829 cytosol | IBA GO_REF:0000033 | ACCEPT | Summary: GIGYF2 acts in the cytosol on translating mRNAs. Well supported and consistent with IDA evidence. Reason: Cytosolic activity is expected for a translational-repression/mRNA-decay adaptor and is supported by direct localization data. Supporting Evidence: file:human/GIGYF2/GIGYF2-uniprot.txt assists ribosome-associated |
| GO:0031982 vesicle | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: Vesicle localization, phylogenetically inferred. GIGYF2 is found in endosomal compartments in brain, but vesicle is not its primary functional site. Reason: GIGYF2 was reported in endosomal compartments in brain (PMID:20670374); a vesicle/endosome association is plausible but peripheral to its translational repression role. Supporting Evidence: PMID:20670374 GIGYF2 is present in endosomal compartments in the mammalian brains and enhances IGF-1-induced ERK1/2 activation. |
| GO:0043204 perikaryon | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: Neuronal perikaryon localization, phylogenetically inferred and supported by IDA in brain. Relevant to GIGYF2's neuronal roles. Reason: GIGYF2 localizes to neuronal perikarya and proximal dendrites (PMID:20670374); a cell-type-specific localization rather than a core molecular site. Supporting Evidence: PMID:20670374 localised in neuronal perikarya and proximal dendrites. |
| GO:0048009 insulin-like growth factor receptor signaling pathway | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: Legacy GRB10-linked role modulating IGF-1 receptor signaling. Real but secondary to the translational-repression/RQC function. Reason: GIGYF2 enhances IGF-1-induced ERK signaling via GRB10, but the dominant, broadly conserved function is translational repression in the 4EHP-GYF2 complex. Supporting Evidence: PMID:20670374 enhances IGF-1-induced ERK1/2 activation. |
| GO:1990635 proximal dendrite | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: Proximal dendrite localization, supported by IDA in neurons. Relevant to local translational control in dendrites. Reason: GIGYF2 localizes to proximal dendrites of neurons (PMID:20670374), consistent with a role in local translational repression; a cell-type-specific site. Supporting Evidence: PMID:20670374 localised in neuronal perikarya and proximal dendrites. |
| GO:0005515 protein binding | IPI PMID:15161933 Comprehensive proteomic analysis of interphase and mitotic 1... | KEEP AS NON CORE | Summary: Generic IPI protein-binding annotation. Records an interaction but the term is uninformative; informative interactions (EIF4E2, DDX6) are captured elsewhere. Reason: 'protein binding' does not convey GIGYF2's molecular function. Supporting Evidence: file:human/GIGYF2/GIGYF2-goa.tsv PMID:15161933 |
| 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 a ubiquitin-signaling interaction dataset. Uninformative as a molecular function. Reason: Records a real interaction but the generic term is not elevated to core. Supporting Evidence: file:human/GIGYF2/GIGYF2-goa.tsv PMID:28698298 |
| GO:0005515 protein binding | IPI PMID:35271311 OpenCell: Endogenous tagging for the cartography of human ce... | KEEP AS NON CORE | Summary: Generic IPI protein-binding annotation. Uninformative as a molecular function. Reason: Records a real interaction but the generic term provides no functional insight. Supporting Evidence: file:human/GIGYF2/GIGYF2-goa.tsv PMID:35271311 |
| GO:0005737 cytoplasm | IEA GO_REF:0000107 | ACCEPT | Summary: Cytoplasmic localization (IEA). Consistent with the well-established cytosolic activity of GIGYF2. Reason: GIGYF2 is a cytoplasmic mRNA-associated protein; cytoplasm localization is well supported. Supporting Evidence: file:human/GIGYF2/GIGYF2-uniprot.txt assists ribosome-associated |
| GO:0016020 membrane | IEA GO_REF:0000107 | MARK AS OVER ANNOTATED | Summary: Generic 'membrane' localization (IEA). GIGYF2 is not an integral membrane protein. Reason: No transmembrane domain; the informative localizations are cytosol, stress granules and P-bodies. Supporting Evidence: file:human/GIGYF2/GIGYF2-uniprot.txt Key component of the 4EHP-GYF2 complex, a multiprotein |
| GO:0031982 vesicle | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Vesicle localization (IEA), corroborated by endosomal localization in brain. Reason: Peripheral vesicle/endosome association reported in neurons; not the core site. Supporting Evidence: PMID:20670374 GIGYF2 is present in endosomal compartments in the mammalian brains and enhances IGF-1-induced ERK1/2 activation. |
| GO:0043204 perikaryon | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Perikaryon localization (IEA), corroborated by IDA in neurons. Reason: Cell-type-specific neuronal localization, supported experimentally. Supporting Evidence: PMID:20670374 localised in neuronal perikarya and proximal dendrites. |
| GO:1990635 proximal dendrite | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Proximal dendrite localization (IEA), corroborated by IDA in neurons. Reason: Cell-type-specific neuronal localization, supported experimentally. Supporting Evidence: PMID:20670374 localised in neuronal perikarya and proximal dendrites. |
| GO:0005829 cytosol | IDA GO_REF:0000052 | ACCEPT | Summary: Direct (immunofluorescence) cytosol localization. Consistent with GIGYF2's cytosolic activity. Reason: Cytosolic localization is experimentally supported and matches its function. Supporting Evidence: file:human/GIGYF2/GIGYF2-uniprot.txt assists ribosome-associated |
| GO:1990261 pre-mRNA catabolic process | NAS PMID:33053355 4EHP and GIGYF1/2 Mediate Translation-Coupled Messenger RNA ... | MODIFY | Summary: ComplexPortal-derived annotation reflecting the 4EHP-GIGYF2 co-translational mRNA-decay complex. The biology (decay of translated, ribosome-stalled mRNAs) is correct, but 'pre-mRNA catabolic process' is imprecise; substrates are mature mRNAs. Reason: The complex triggers co-translational decay of mature mRNAs, not pre-mRNA turnover; a mature-mRNA catabolic term better reflects the evidence. Proposed replacements: nuclear-transcribed mRNA catabolic process Supporting Evidence: PMID:33053355 4EHP and GIGYF1/2 Mediate Translation-Coupled Messenger RNA Decay. |
| GO:0045947 negative regulation of translational initiation | IDA PMID:32726578 GIGYF2 and 4EHP Inhibit Translation Initiation of Defective ... | ACCEPT | Summary: Direct evidence that GIGYF2 (with 4EHP) inhibits translation initiation on ribosome-stalling mRNAs as a negative-feedback RQC mechanism. Core function. Reason: CRISPR screening and reporter assays show GIGYF2/4EHP specifically inhibit initiation on defective messages. Supporting Evidence: PMID:32726578 This negative feedback loop is mediated by two translation inhibitors, GIGYF2 and 4EHP. |
| GO:0045947 negative regulation of translational initiation | IDA PMID:35878012 SARS-CoV-2 impairs interferon production via NSP2-induced re... | ACCEPT | Summary: Direct evidence that GIGYF2/4EHP repress translation initiation of IFNB1 mRNA, co-opted by SARS-CoV-2 nsp2. Supports the core repressor function. Reason: GIGYF2/4EHP repress Ifnb1 translation; nsp2 enhances GIGYF2-EIF4E2 binding to increase this repression. Supporting Evidence: PMID:35878012 Here, we document a mechanism by which the NSP2 protein impedes IFN-Ξ² expression through translational repression of Ifnb1 mRNA by coopting the GIGYF2/4EHP complex |
| GO:0060090 molecular adaptor activity | IDA PMID:32726578 GIGYF2 and 4EHP Inhibit Translation Initiation of Defective ... | ACCEPT | Summary: GIGYF2 functions as a molecular adaptor that bridges EIF4E2 to RNA-associated factors and ZNF598/RQC machinery. Core molecular function. Reason: GIGYF2 bridges EIF4E2 to ZFP36/TTP, DDX6 and the RQC apparatus; an adaptor MF is appropriate and informative. Supporting Evidence: file:human/GIGYF2/GIGYF2-uniprot.txt acts as a factor that bridges EIF4E2 to ZFP36/TTP, linking |
| GO:0060090 molecular adaptor activity | IDA PMID:35878012 SARS-CoV-2 impairs interferon production via NSP2-induced re... | ACCEPT | Summary: GIGYF2 adaptor activity bridging EIF4E2 and nsp2/RNA factors to repress IFNB1. Supports the adaptor MF. Reason: nsp2 co-opts the GIGYF2 adaptor to recruit 4EHP to IFNB1 mRNA, consistent with a bridging/adaptor function. Supporting Evidence: PMID:35878012 Here, we document a mechanism by which the NSP2 protein impedes IFN-Ξ² expression through translational repression of Ifnb1 mRNA by coopting the GIGYF2/4EHP complex |
| GO:0060339 negative regulation of type I interferon-mediated signaling pathway | IDA PMID:35878012 SARS-CoV-2 impairs interferon production via NSP2-induced re... | KEEP AS NON CORE | Summary: GIGYF2/4EHP repress IFNB1 (type I IFN) translation; this is the basis of nsp2's immune evasion. A genuine, though context-specific, role. Reason: The IFN-repression role is a specific consequence of GIGYF2's general translational repression activity acting on IFNB1 mRNA, exploited during SARS-CoV-2 infection; relevant but not the core, ubiquitous function. Supporting Evidence: PMID:35878012 Here, we document a mechanism by which the NSP2 protein impedes IFN-Ξ² expression through translational repression of Ifnb1 mRNA by coopting the GIGYF2/4EHP complex |
| GO:0072344 rescue of stalled cytosolic ribosome | IDA PMID:32726578 GIGYF2 and 4EHP Inhibit Translation Initiation of Defective ... | ACCEPT | Summary: GIGYF2/4EHP participate in ribosome-associated quality control by suppressing new initiation on mRNAs that stall ribosomes, working in concert with RQC degradation pathways. Core RQC function. Reason: Direct evidence places GIGYF2/4EHP in the RQC response to stalled ribosomes, acting in parallel with degradation of the stalled nascent chain. Supporting Evidence: PMID:32726578 GIGYF2 and 4EHP Inhibit Translation Initiation of Defective Messenger RNAs to Assist Ribosome-Associated Quality Control. file:human/GIGYF2/GIGYF2-uniprot.txt assists ribosome-associated quality control |
| GO:0005515 protein binding | IPI PMID:31439631 Molecular basis for GIGYF-Me31B complex assembly in 4EHP-med... | MODIFY | Summary: IPI annotation capturing the structurally defined direct interactions of GIGYF2 with EIF4E2, ZFP36/TTP and DDX6. Functionally central but 'protein binding' is too generic. Reason: The interactions defined here (EIF4E2 via 4EHP-binding motif; DDX6 via a dedicated motif; TTP via P-P-P-P-G repeats) underlie translational repression; a specific eIF4E-binding / repression MF is more informative than generic protein binding. Proposed replacements: eukaryotic initiation factor 4E binding Supporting Evidence: file:human/GIGYF2/GIGYF2-uniprot.txt Interacts (via the 4EHP-binding motif) with EIF4E2; |
| GO:0045296 cadherin binding | HDA PMID:25468996 E-cadherin interactome complexity and robustness resolved by... | MARK AS OVER ANNOTATED | Summary: 'cadherin binding' from a high-throughput proximity/affinity proteomics dataset. There is no functional evidence that cadherin binding is part of GIGYF2 biology. Reason: This term commonly arises as an artifact of HT BioID/AP-MS proximity datasets and does not reflect a characterized GIGYF2 function. Supporting Evidence: file:human/GIGYF2/GIGYF2-goa.tsv PMID:25468996 |
| 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 an EGFR-Akt/RQCD1 study. Uninformative as a molecular function. Reason: Records interactions in a signaling-network context but the generic term is not elevated. Supporting Evidence: PMID:20878056 Critical involvement of RQCD1 in the EGFR-Akt pathway in mammary carcinogenesis. |
| GO:0032991 protein-containing complex | IDA PMID:20878056 Critical involvement of RQCD1 in the EGFR-Akt pathway in mam... | KEEP AS NON CORE | Summary: Generic complex membership. GIGYF2 is a bona fide complex component (4EHP-GYF2), but the top-level term is uninformative. Reason: The specific complex (4EHP-GIGYF2-DDX6/ZNF598) is captured by the functional annotations; 'protein-containing complex' conveys no specific information. Supporting Evidence: PMID:20878056 Critical involvement of RQCD1 in the EGFR-Akt pathway in mammary carcinogenesis. |
| GO:0005515 protein binding | IPI PMID:20670374 GIGYF2 is present in endosomal compartments in the mammalian... | KEEP AS NON CORE | Summary: Generic protein-binding annotation from the brain IGF/endosome study. Uninformative as a molecular function. Reason: Records a real interaction but the generic term is not elevated. Supporting Evidence: PMID:20670374 GIGYF2 is present in endosomal compartments in the mammalian brains and enhances IGF-1-induced ERK1/2 activation. |
| GO:0005515 protein binding | IPI PMID:20696395 Conserved beta-hairpin recognition by the GYF domains of Smy... | KEEP AS NON CORE | Summary: Generic protein-binding annotation from the GYF-domain proline-rich-sequence recognition study. The specific MF (proline-rich region binding) is captured separately. Reason: Records the GYF-domain PRS interaction; the informative MF is GO:0070064. Supporting Evidence: PMID:20696395 Conserved beta-hairpin recognition by the GYF domains of Smy2 and GIGYF2 in mRNA surveillance and vesicular transport complexes. |
| GO:0005515 protein binding | IPI PMID:27157137 Post-transcriptional gene silencing activity of human GIGYF2... | KEEP AS NON CORE | Summary: Generic protein-binding annotation from the AGO2/miRNA silencing study. The functional outcome (silencing/destabilization) is captured by other terms. Reason: Records the GIGYF2-AGO2 interaction; the generic term is not elevated. Supporting Evidence: PMID:27157137 upon tethering to a reporter mRNA, GIGYF2 exhibits strong, dose-dependent silencing activity, involving both mRNA destabilization and translational repression. |
| GO:0005768 endosome | IDA PMID:20670374 GIGYF2 is present in endosomal compartments in the mammalian... | KEEP AS NON CORE | Summary: Endosome localization in brain (IDA). A genuine but peripheral localization. Reason: GIGYF2 was found in endosomal compartments in brain; relevant to its neuronal/IGF role but not its core translational-repression site. Supporting Evidence: PMID:20670374 GIGYF2 is present in endosomal compartments in the mammalian brains and enhances IGF-1-induced ERK1/2 activation. |
| GO:0005783 endoplasmic reticulum | IDA PMID:20696395 Conserved beta-hairpin recognition by the GYF domains of Smy... | KEEP AS NON CORE | Summary: ER localization reported alongside GYF-domain studies. GIGYF2 is mainly cytosolic; ER association is likely peripheral (e.g. at ER-bound translation sites). Reason: Peripheral ER association is plausible for a translation-associated factor but is not its defining site. Supporting Evidence: PMID:20696395 Conserved beta-hairpin recognition by the GYF domains of Smy2 and GIGYF2 in mRNA surveillance and vesicular transport complexes. |
| GO:0005794 Golgi apparatus | IDA PMID:20696395 Conserved beta-hairpin recognition by the GYF domains of Smy... | KEEP AS NON CORE | Summary: Golgi localization reported alongside GYF-domain studies. GIGYF2 is mainly cytosolic; Golgi association is peripheral. Reason: Not the defining functional site; a peripheral localization. Supporting Evidence: PMID:20696395 Conserved beta-hairpin recognition by the GYF domains of Smy2 and GIGYF2 in mRNA surveillance and vesicular transport complexes. |
| GO:0010494 cytoplasmic stress granule | IDA PMID:20696395 Conserved beta-hairpin recognition by the GYF domains of Smy... | ACCEPT | Summary: Stress granule localization (IDA). Consistent with GIGYF2's role in translational repression and mRNA storage/decay. Reason: GIGYF2 partitions into stress granules, consistent with its repressed-mRNP associations. Supporting Evidence: PMID:20696395 Conserved beta-hairpin recognition by the GYF domains of Smy2 and GIGYF2 in mRNA surveillance and vesicular transport complexes. |
| GO:0016441 post-transcriptional gene silencing | IDA PMID:27157137 Post-transcriptional gene silencing activity of human GIGYF2... | ACCEPT | Summary: GIGYF2 is a silencing effector in the miRNA/AGO2 pathway, repressing translation and destabilizing target mRNAs when tethered. Reason: Tethering assays show strong, dose-dependent silencing by GIGYF2 via the AGO2/miRNA pathway. Supporting Evidence: PMID:27157137 upon tethering to a reporter mRNA, GIGYF2 exhibits strong, dose-dependent silencing activity, involving both mRNA destabilization and translational repression. |
| GO:0043204 perikaryon | IDA PMID:20670374 GIGYF2 is present in endosomal compartments in the mammalian... | KEEP AS NON CORE | Summary: Direct neuronal perikaryon localization. Relevant to neuronal function. Reason: Cell-type-specific neuronal localization supported by direct evidence. Supporting Evidence: PMID:20670374 localised in neuronal perikarya and proximal dendrites. |
| GO:0048009 insulin-like growth factor receptor signaling pathway | IMP PMID:20670374 GIGYF2 is present in endosomal compartments in the mammalian... | KEEP AS NON CORE | Summary: IMP evidence that GIGYF2 modulates IGF-1 receptor/ERK signaling. Legacy GRB10-linked role; secondary to translational repression. Reason: GIGYF2 enhances IGF-1-induced ERK activation, but its dominant conserved function is translational repression. Supporting Evidence: PMID:20670374 enhances IGF-1-induced ERK1/2 activation. |
| GO:0061157 mRNA destabilization | IDA PMID:27157137 Post-transcriptional gene silencing activity of human GIGYF2... | ACCEPT | Summary: GIGYF2 destabilizes target mRNAs (in addition to repressing their translation), consistent with coupling repression to decay via DDX6/decapping. Reason: Tethered GIGYF2 causes mRNA destabilization; this is a genuine functional output. Supporting Evidence: PMID:27157137 upon tethering to a reporter mRNA, GIGYF2 exhibits strong, dose-dependent silencing activity, involving both mRNA destabilization and translational repression. |
| GO:0070064 proline-rich region binding | IDA PMID:20696395 Conserved beta-hairpin recognition by the GYF domains of Smy... | ACCEPT | Summary: The GYF domain of GIGYF2 recognizes proline-rich sequences in partner proteins, mediating recruitment to mRNA-surveillance/transport complexes. Informative MF. Reason: Direct structural evidence that the GIGYF2 GYF domain binds proline-rich sequences (PRS), the basis of its adaptor interactions. Supporting Evidence: PMID:20696395 Conserved beta-hairpin recognition by the GYF domains of Smy2 and GIGYF2 in mRNA surveillance and vesicular transport complexes. |
| GO:1990635 proximal dendrite | IDA PMID:20670374 GIGYF2 is present in endosomal compartments in the mammalian... | KEEP AS NON CORE | Summary: Direct proximal-dendrite localization in neurons. Reason: Cell-type-specific neuronal localization supported by direct evidence; consistent with local translational control. Supporting Evidence: PMID:20670374 localised in neuronal perikarya and proximal dendrites. |
| GO:0016020 membrane | HDA PMID:19946888 Defining the membrane proteome of NK cells. | MARK AS OVER ANNOTATED | Summary: 'membrane' from a high-throughput proteomics dataset. GIGYF2 is not an integral membrane protein. Reason: No transmembrane domain; HT membrane-fraction co-purification does not establish a functional membrane localization. Supporting Evidence: file:human/GIGYF2/GIGYF2-goa.tsv PMID:19946888 |
| GO:0003723 RNA binding | HDA PMID:22681889 The mRNA-bound proteome and its global occupancy profile on ... | ACCEPT | Summary: RNA binding from a proteome-wide mRNA-interactome capture study. Consistent with GIGYF2's association with target mRNAs and ribosomes. Reason: GIGYF2 was identified as an mRNA-bound protein, consistent with its co-translational binding to target transcripts. Supporting Evidence: file:human/GIGYF2/GIGYF2-goa.tsv PMID:22681889 |
| GO:0017148 negative regulation of translation | IMP PMID:22751931 A novel 4EHP-GIGYF2 translational repressor complex is essen... | ACCEPT | Summary: Genetic/biochemical evidence that the 4EHP-GIGYF2 complex represses translation; its disruption increases translation and causes perinatal lethality in mice. Core. Reason: Disruption of the m4EHP-GIGYF2 complex leads to increased translation, directly demonstrating GIGYF2's negative regulation of translation. Supporting Evidence: PMID:22751931 Disruption of the m4EHP-GIGYF2 complex leads to increased translation and perinatal lethality in mice. |
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Download this section (compressed HTML)Q: Which endogenous mRNAs depend on GIGYF2 (versus GIGYF1) for RQC-coupled repression, and how is target selection partitioned between ZNF598-, TTP- and miRNA-directed recruitment?
Q: How do GIGYF2 loss-of-function variants produce neurodevelopmental/neuropsychiatric phenotypes - via failure of RQC-coupled repression, dysregulated dendritic translation, or altered IGF signaling?
Experiment: Ribosome profiling plus mRNA stability measurements in GIGYF2 knockout cells (and 4EHP-binding-motif or GYF-domain separation-of-function mutants) to define target mRNAs and the contribution of each interaction.
Experiment: Reconstitution of the 4EHP-GIGYF2-ZNF598 module on stalled-ribosome substrates to test whether GIGYF2 directly couples collision sensing to initiation shutdown.
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