{"gene":"NUFIP2","run_date":"2026-06-10T05:19:52","timeline":{"discoveries":[{"year":2003,"finding":"NUFIP2 (82-FIP) was identified as a novel FMRP-interacting protein. FMRP interacts with NUFIP2 through a novel interaction motif located in its N-terminal region. NUFIP2 is associated with polyribosomes as a component of mRNP complexes containing FMRP. Subcellular distribution of NUFIP2 is cell cycle-dependent in cultured cells, appearing in both nucleus and cytoplasm in some neurons and only cytoplasmic in others.","method":"Co-immunoprecipitation, yeast two-hybrid, subcellular fractionation, immunofluorescence microscopy","journal":"Human molecular genetics","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP, subcellular fractionation, multiple orthogonal methods; foundational discovery paper replicated by subsequent studies","pmids":["12837692"],"is_preprint":false},{"year":2006,"finding":"The N-terminal domain of FMRP (NDF) adopts a composite fold comprising two Tudor motif repeats followed by a short alpha helix. The second, more flexible Tudor repeat is responsible for interacting with NUFIP2 (82-FIP). The NDF fold contains a 3D nucleolar localization signal, such that destabilization of the fold leads to altered nucleolar localization of FMRP, suggesting an allosteric mechanism regulates FMRP functions including its interaction with NUFIP2.","method":"NMR structure determination, mutagenesis, functional localization assays","journal":"Structure","confidence":"High","confidence_rationale":"Tier 1 / Strong — NMR structure with mutagenesis and functional validation of localization consequences","pmids":["16407062"],"is_preprint":false},{"year":2015,"finding":"NUFIP2 interacts with the RNA helicase DDX6 in an RNA-independent manner. NUFIP2 is not a P-body component but re-localizes to stress granules upon cellular stress exposure, suggesting a function in translation repression during the stress response.","method":"Immunoprecipitation with nuclease digestion (RNA-independent pulldown), mass spectrometry, immunofluorescence microscopy","journal":"Biomolecules","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — RNA-independent Co-IP confirmed by MS, stress granule localization validated by imaging; single lab","pmids":["26184334"],"is_preprint":false},{"year":2018,"finding":"NUFIP2 was identified as a cofactor of Roquin-1/Roquin-2-induced mRNA decay. NUFIP2 binds directly and with high affinity to Roquin, and Roquin stabilizes NUFIP2 in cells. NUFIP2 and Roquin cooperatively bind non-canonical stem-loop structures in the ICOS 3'-UTR and in the Ox40 3'-UTR tandem loop element to mediate post-transcriptional repression of ICOS mRNA. Knockdown of NUFIP2 identified by siRNA screen (~1500 genes) impaired Roquin-induced mRNA decay.","method":"siRNA screen, direct binding assay (high-affinity interaction), co-immunoprecipitation, RNA electrophoretic mobility shift assay, reporter assays","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Strong — direct binding demonstrated, cooperative binding to RNA element shown, functional mRNA decay rescue, multiple orthogonal methods in one study","pmids":["29352114"],"is_preprint":false},{"year":2018,"finding":"NUFIP2 associates with stress granule-localized proteins including DDX1, ATXN2, ATXN2L, and FAM98A, as shown by co-immunoprecipitation in the context of stress granule biology.","method":"Co-immunoprecipitation","journal":"Molecular and cellular biochemistry","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single Co-IP experiment, NUFIP2 is a secondary finding in a paper focused on FAM98A","pmids":["29992460"],"is_preprint":false},{"year":2020,"finding":"NUFIP2 was identified as an FMRP-interacting protein by affinity pull-down and quantitative LC-MS/MS analysis. NUFIP2 interacts with the N-terminus of FMRP (among 28 proteins interacting with the N-terminal domain). FMRP interactome studies placed NUFIP2 within networks associated with RNA metabolism and ribonucleoprotein stress granule formation.","method":"Affinity pull-down, quantitative LC-MS/MS proteomics","journal":"The FEBS journal","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — quantitative MS-based interactome with domain mapping; single lab, confirms prior interaction findings","pmids":["32525608"],"is_preprint":false},{"year":2022,"finding":"Upon lysosomal damage, NUFIP2 is recruited to damaged lysosomes together with G3BP1 and GABARAP-family mATG8 proteins. GABARAPs interact directly with NUFIP2, and Atg8ylation (membrane conjugation of mATG8s) is required for NUFIP2 recruitment to damaged lysosomes. At the lysosome, NUFIP2 contributes to MTOR inactivation together with LGALS8 (galectin-8) via the Ragulator-RRAGA-RRAGB complex. This function is separable from NUFIP2's role in stress granule formation and is governed by GABARAP and Atg8ylation.","method":"Lysosome immunopurification (LysoIP), proximity proteomics, co-immunoprecipitation, MTOR activity assays, genetic knockdown with functional readout","journal":"Autophagy","confidence":"High","confidence_rationale":"Tier 2 / Strong — direct interaction (Co-IP), lysosome purification, functional MTOR readout, Atg8ylation-dependence shown with multiple orthogonal approaches","pmids":["36394332"],"is_preprint":false},{"year":2025,"finding":"NUFIP2 is the primary interactor of ATXN2L as identified by co-immunoprecipitation in wild-type murine embryonic fibroblasts. NUFIP2 protein levels are depleted in ATXN2L-null fibroblasts as shown by proteome profiling. In a SCA2 mouse model (Atxn2-CAG100-KnockIn), NUFIP2 homodimers accumulate in aged spinal cord tissues during ATXN2 aggregation, suggesting NUFIP2 is sequestered during pathological ATXN2 aggregation.","method":"Co-immunoprecipitation in wild-type and ATXN2L-null cells, mass spectrometry proteomics, SCA2 mouse model tissue analysis","journal":"Neurobiology of disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP with null cell controls, quantitative proteomics, in vivo model validation; single lab","pmids":["40220918"],"is_preprint":false},{"year":2025,"finding":"NUFIP2 was identified as a TDP-43 interactor specifically associated with TDP-43 cytoplasmic mislocalization conditions (not under normal nuclear conditions). NUFIP2 sequesters TDP-43 into cytoplasmic aggregates and co-localizes with TDP-43 pathology in ALS/FTLD patient tissue.","method":"APEX2-driven proximity labeling, mass spectrometry, functional screen, immunofluorescence in patient tissue","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — proximity labeling with context-dependent conditions, functional validation in patient tissue; preprint, not yet peer-reviewed","pmids":["40291645"],"is_preprint":true},{"year":2025,"finding":"O-GlcNAcylation of NUFIP2 regulates the formation of RNA-protein biocondensates (stress granules). Site mutagenesis and inhibition of O-GlcNAc transferase combined with fluorescence microscopy validated that O-GlcNAcylation promotes NUFIP2 condensate formation during stress recovery.","method":"Mass spectrometry-based chemoproteomics, site mutagenesis, O-GlcNAc transferase inhibition, fluorescence microscopy","journal":"Nature communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — site mutagenesis with functional condensate readout, OGT inhibition, imaging; single lab, NUFIP2 is one of several validated proteins","pmids":["40307207"],"is_preprint":false}],"current_model":"NUFIP2 is a multifunctional RNA-binding protein cofactor that interacts directly with FMRP (via FMRP's second Tudor repeat), serves as a cofactor for Roquin-induced mRNA decay by cooperatively binding non-canonical stem-loop structures in target 3'-UTRs (e.g., ICOS, Ox40), interacts with the RNA helicase DDX6, localizes to stress granules under cellular stress in a manner regulated by O-GlcNAcylation, is recruited to damaged lysosomes via direct GABARAP interaction to contribute to MTOR inactivation through the Ragulator-Rag complex, and interacts with ATXN2L and TDP-43 in contexts relevant to neurodegeneration."},"narrative":{"mechanistic_narrative":"NUFIP2 is a multifunctional RNA-binding protein cofactor that operates at the interface of post-transcriptional regulation, stress-responsive ribonucleoprotein condensates, and lysosomal stress signaling [PMID:12837692, PMID:29352114, PMID:36394332]. It was first defined as an FMRP-interacting protein (82-FIP) associated with polyribosomes within FMRP-containing mRNP complexes [PMID:12837692], with structural work localizing the interaction to the second, flexible Tudor repeat of FMRP's N-terminal domain, whose fold also encodes a nucleolar localization signal that allosterically couples FMRP localization to its protein interactions [PMID:16407062]. As a cofactor of Roquin-1/Roquin-2-induced mRNA decay, NUFIP2 binds Roquin directly and with high affinity and the two cooperatively recognize non-canonical stem-loop structures in target 3'-UTRs such as those of ICOS and Ox40 to drive post-transcriptional repression, with Roquin reciprocally stabilizing NUFIP2 in cells [PMID:29352114]. NUFIP2 interacts RNA-independently with the helicase DDX6 and relocalizes to stress granules upon cellular stress, consistent with a role in translational repression [PMID:26184334]; its incorporation into stress-granule condensates is promoted by O-GlcNAcylation during stress recovery [PMID:40307207]. Distinct from its condensate function, NUFIP2 is recruited to damaged lysosomes through direct binding to GABARAP-family mATG8 proteins in an Atg8ylation-dependent manner, where it cooperates with galectin-8 to inactivate MTOR via the Ragulator-Rag complex [PMID:36394332]. NUFIP2 is the primary interactor of ATXN2L and is depleted in ATXN2L-null cells, and it is captured into pathological aggregates with ATXN2 and with cytoplasmically mislocalized TDP-43 in neurodegeneration contexts [PMID:40220918].","teleology":[{"year":2003,"claim":"Establishing what NUFIP2 does began with identifying its physical partner, defining it as an FMRP-associated, polyribosome-bound mRNP component rather than an orphan protein.","evidence":"Co-IP, yeast two-hybrid, subcellular fractionation, and immunofluorescence in cultured cells and neurons","pmids":["12837692"],"confidence":"High","gaps":["RNA targets bound by NUFIP2 not defined","functional consequence of the FMRP association on translation not established"]},{"year":2006,"claim":"Structural definition of the FMRP N-terminal domain pinpointed the second Tudor repeat as the NUFIP2 contact and linked fold stability to FMRP localization, providing a molecular basis for the interaction.","evidence":"NMR structure determination with mutagenesis and localization assays","pmids":["16407062"],"confidence":"High","gaps":["NUFIP2 region engaging the Tudor repeat not mapped","functional output of the regulated interaction not resolved"]},{"year":2015,"claim":"Linking NUFIP2 to a translational-repression machinery showed it binds DDX6 RNA-independently and partitions into stress granules, not P-bodies, under stress.","evidence":"RNA-independent Co-IP with mass spectrometry and immunofluorescence","pmids":["26184334"],"confidence":"Medium","gaps":["functional role of the DDX6 interaction in repression not directly tested","single-lab finding"]},{"year":2018,"claim":"An unbiased screen assigned NUFIP2 a defined post-transcriptional function as a Roquin cofactor that cooperatively recognizes non-canonical 3'-UTR stem-loops to drive mRNA decay.","evidence":"siRNA screen, direct binding and RNA EMSA, Co-IP, and reporter decay assays for ICOS/Ox40 elements","pmids":["29352114"],"confidence":"High","gaps":["full set of NUFIP2-dependent Roquin targets unknown","structural basis of cooperative RNA recognition not solved"]},{"year":2018,"claim":"Co-IP placed NUFIP2 within a broader stress-granule protein network including ATXN2/ATXN2L and FAM98A.","evidence":"Co-immunoprecipitation (NUFIP2 a secondary finding)","pmids":["29992460"],"confidence":"Low","gaps":["single Co-IP without reciprocal validation","direct versus indirect associations not distinguished"]},{"year":2020,"claim":"Quantitative interactome mapping confirmed NUFIP2 as an N-terminal FMRP interactor embedded in RNA-metabolism and stress-granule networks.","evidence":"Affinity pull-down with quantitative LC-MS/MS and domain mapping","pmids":["32525608"],"confidence":"Medium","gaps":["functional consequence of network membership not tested","single-lab dataset"]},{"year":2022,"claim":"A new, condensate-independent role emerged: NUFIP2 is recruited to damaged lysosomes via direct GABARAP binding and contributes to MTOR inactivation through the Ragulator-Rag complex.","evidence":"LysoIP, proximity proteomics, Co-IP, and MTOR activity assays with Atg8ylation-dependence","pmids":["36394332"],"confidence":"High","gaps":["how NUFIP2 mechanistically promotes MTOR inactivation at the lysosome unresolved","relationship between RNA-binding activity and lysosomal function unclear"]},{"year":2025,"claim":"NUFIP2 was defined as the primary ATXN2L interactor whose levels depend on ATXN2L and which is sequestered as homodimers during pathological ATXN2 aggregation, connecting it to neurodegeneration.","evidence":"Reciprocal Co-IP in ATXN2L-null cells, proteome profiling, and SCA2 mouse spinal cord analysis","pmids":["40220918"],"confidence":"Medium","gaps":["functional consequence of NUFIP2 sequestration on neuronal physiology not established","single-lab"]},{"year":2025,"claim":"Context-dependent proximity labeling identified NUFIP2 as a TDP-43 interactor that sequesters mislocalized TDP-43 into cytoplasmic aggregates seen in ALS/FTLD tissue.","evidence":"APEX2 proximity labeling, mass spectrometry, functional screen, and patient-tissue immunofluorescence (preprint)","pmids":["40291645"],"confidence":"Medium","gaps":["not yet peer-reviewed","directness of NUFIP2-TDP-43 interaction not established"]},{"year":2025,"claim":"A post-translational regulatory layer was added by showing O-GlcNAcylation of NUFIP2 promotes its incorporation into stress-granule biocondensates during stress recovery.","evidence":"Chemoproteomics, site mutagenesis, OGT inhibition, and fluorescence microscopy","pmids":["40307207"],"confidence":"Medium","gaps":["modified residues' impact on RNA binding and Roquin/DDX6 functions not tested","single-lab"]},{"year":null,"claim":"How NUFIP2's distinct activities — Roquin-dependent mRNA decay, stress-granule condensation, and lysosomal MTOR control — are integrated or switched within a cell remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["no unifying structural or regulatory model linking the functions","intrinsic RNA-binding specificity of NUFIP2 alone not defined","in vivo physiological role in immunity versus neurodegeneration not reconciled"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0003723","term_label":"RNA binding","supporting_discovery_ids":[0,3]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[3,6]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[6]}],"localization":[{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[2]},{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[0]},{"term_id":"GO:0005764","term_label":"lysosome","supporting_discovery_ids":[6]},{"term_id":"GO:0005840","term_label":"ribosome","supporting_discovery_ids":[0]}],"pathway":[{"term_id":"R-HSA-8953854","term_label":"Metabolism of RNA","supporting_discovery_ids":[3]},{"term_id":"R-HSA-8953897","term_label":"Cellular responses to stimuli","supporting_discovery_ids":[2,9]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[6]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[3]}],"complexes":["stress granule"],"partners":["FMRP","DDX6","RC3H1","ATXN2L","GABARAP","TARDBP","ATXN2","FAM98A"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q7Z417","full_name":"FMR1-interacting protein NUFIP2","aliases":["82 kDa FMRP-interacting protein","82-FIP","Cell proliferation-inducing gene 1 protein","FMRP-interacting protein 2","Nuclear FMR1-interacting protein 2"],"length_aa":695,"mass_kda":76.1,"function":"Binds RNA","subcellular_location":"Nucleus; Cytoplasm; Cytoplasm, Stress granule","url":"https://www.uniprot.org/uniprotkb/Q7Z417/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/NUFIP2","classification":"Not Classified","n_dependent_lines":40,"n_total_lines":1208,"dependency_fraction":0.033112582781456956},"opencell":{"profiled":true,"resolved_as":"","ensg_id":"ENSG00000108256","cell_line_id":"CID001517","localizations":[{"compartment":"cytoplasmic","grade":3}],"interactors":[{"gene":"DDX6","stoichiometry":10.0},{"gene":"RPS16","stoichiometry":4.0},{"gene":"ATG13","stoichiometry":0.2},{"gene":"ATG4B","stoichiometry":0.2},{"gene":"ATXN2L","stoichiometry":0.2},{"gene":"CAPRIN1","stoichiometry":0.2},{"gene":"CAPZB","stoichiometry":0.2},{"gene":"DRG1","stoichiometry":0.2},{"gene":"EIF2S3","stoichiometry":0.2},{"gene":"EIF3B","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/target/CID001517","total_profiled":1310},"omim":[{"mim_id":"609356","title":"NUCLEAR FMRP-INTERACTING PROTEIN 2; NUFIP2","url":"https://www.omim.org/entry/609356"},{"mim_id":"309550","title":"FRAGILE X MESSENGER RIBONUCLEOPROTEIN 1; FMR1","url":"https://www.omim.org/entry/309550"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Nucleoplasm","reliability":"Supported"},{"location":"Nuclear bodies","reliability":"Additional"},{"location":"Cytosol","reliability":"Additional"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in all","driving_tissues":[{"tissue":"bone marrow","ntpm":75.4}],"url":"https://www.proteinatlas.org/search/NUFIP2"},"hgnc":{"alias_symbol":["KIAA1321","MGC117262","PIG1","182-FIP","FIP-82","82-FIP","NUFP2"],"prev_symbol":[]},"alphafold":{"accession":"Q7Z417","domains":[],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q7Z417","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q7Z417-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q7Z417-F1-predicted_aligned_error_v6.png","plddt_mean":47.66},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=NUFIP2","jax_strain_url":"https://www.jax.org/strain/search?query=NUFIP2"},"sequence":{"accession":"Q7Z417","fasta_url":"https://rest.uniprot.org/uniprotkb/Q7Z417.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q7Z417/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q7Z417"}},"corpus_meta":[{"pmid":"16407062","id":"PMC_16407062","title":"The structure of the N-terminal domain of the fragile X mental retardation protein: a 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FMRP-interacting protein. FMRP interacts with NUFIP2 through a novel interaction motif located in its N-terminal region. NUFIP2 is associated with polyribosomes as a component of mRNP complexes containing FMRP. Subcellular distribution of NUFIP2 is cell cycle-dependent in cultured cells, appearing in both nucleus and cytoplasm in some neurons and only cytoplasmic in others.\",\n      \"method\": \"Co-immunoprecipitation, yeast two-hybrid, subcellular fractionation, immunofluorescence microscopy\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP, subcellular fractionation, multiple orthogonal methods; foundational discovery paper replicated by subsequent studies\",\n      \"pmids\": [\"12837692\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"The N-terminal domain of FMRP (NDF) adopts a composite fold comprising two Tudor motif repeats followed by a short alpha helix. The second, more flexible Tudor repeat is responsible for interacting with NUFIP2 (82-FIP). The NDF fold contains a 3D nucleolar localization signal, such that destabilization of the fold leads to altered nucleolar localization of FMRP, suggesting an allosteric mechanism regulates FMRP functions including its interaction with NUFIP2.\",\n      \"method\": \"NMR structure determination, mutagenesis, functional localization assays\",\n      \"journal\": \"Structure\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — NMR structure with mutagenesis and functional validation of localization consequences\",\n      \"pmids\": [\"16407062\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"NUFIP2 interacts with the RNA helicase DDX6 in an RNA-independent manner. NUFIP2 is not a P-body component but re-localizes to stress granules upon cellular stress exposure, suggesting a function in translation repression during the stress response.\",\n      \"method\": \"Immunoprecipitation with nuclease digestion (RNA-independent pulldown), mass spectrometry, immunofluorescence microscopy\",\n      \"journal\": \"Biomolecules\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — RNA-independent Co-IP confirmed by MS, stress granule localization validated by imaging; single lab\",\n      \"pmids\": [\"26184334\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"NUFIP2 was identified as a cofactor of Roquin-1/Roquin-2-induced mRNA decay. NUFIP2 binds directly and with high affinity to Roquin, and Roquin stabilizes NUFIP2 in cells. NUFIP2 and Roquin cooperatively bind non-canonical stem-loop structures in the ICOS 3'-UTR and in the Ox40 3'-UTR tandem loop element to mediate post-transcriptional repression of ICOS mRNA. Knockdown of NUFIP2 identified by siRNA screen (~1500 genes) impaired Roquin-induced mRNA decay.\",\n      \"method\": \"siRNA screen, direct binding assay (high-affinity interaction), co-immunoprecipitation, RNA electrophoretic mobility shift assay, reporter assays\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — direct binding demonstrated, cooperative binding to RNA element shown, functional mRNA decay rescue, multiple orthogonal methods in one study\",\n      \"pmids\": [\"29352114\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"NUFIP2 associates with stress granule-localized proteins including DDX1, ATXN2, ATXN2L, and FAM98A, as shown by co-immunoprecipitation in the context of stress granule biology.\",\n      \"method\": \"Co-immunoprecipitation\",\n      \"journal\": \"Molecular and cellular biochemistry\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single Co-IP experiment, NUFIP2 is a secondary finding in a paper focused on FAM98A\",\n      \"pmids\": [\"29992460\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"NUFIP2 was identified as an FMRP-interacting protein by affinity pull-down and quantitative LC-MS/MS analysis. NUFIP2 interacts with the N-terminus of FMRP (among 28 proteins interacting with the N-terminal domain). FMRP interactome studies placed NUFIP2 within networks associated with RNA metabolism and ribonucleoprotein stress granule formation.\",\n      \"method\": \"Affinity pull-down, quantitative LC-MS/MS proteomics\",\n      \"journal\": \"The FEBS journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — quantitative MS-based interactome with domain mapping; single lab, confirms prior interaction findings\",\n      \"pmids\": [\"32525608\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Upon lysosomal damage, NUFIP2 is recruited to damaged lysosomes together with G3BP1 and GABARAP-family mATG8 proteins. GABARAPs interact directly with NUFIP2, and Atg8ylation (membrane conjugation of mATG8s) is required for NUFIP2 recruitment to damaged lysosomes. At the lysosome, NUFIP2 contributes to MTOR inactivation together with LGALS8 (galectin-8) via the Ragulator-RRAGA-RRAGB complex. This function is separable from NUFIP2's role in stress granule formation and is governed by GABARAP and Atg8ylation.\",\n      \"method\": \"Lysosome immunopurification (LysoIP), proximity proteomics, co-immunoprecipitation, MTOR activity assays, genetic knockdown with functional readout\",\n      \"journal\": \"Autophagy\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — direct interaction (Co-IP), lysosome purification, functional MTOR readout, Atg8ylation-dependence shown with multiple orthogonal approaches\",\n      \"pmids\": [\"36394332\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"NUFIP2 is the primary interactor of ATXN2L as identified by co-immunoprecipitation in wild-type murine embryonic fibroblasts. NUFIP2 protein levels are depleted in ATXN2L-null fibroblasts as shown by proteome profiling. In a SCA2 mouse model (Atxn2-CAG100-KnockIn), NUFIP2 homodimers accumulate in aged spinal cord tissues during ATXN2 aggregation, suggesting NUFIP2 is sequestered during pathological ATXN2 aggregation.\",\n      \"method\": \"Co-immunoprecipitation in wild-type and ATXN2L-null cells, mass spectrometry proteomics, SCA2 mouse model tissue analysis\",\n      \"journal\": \"Neurobiology of disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP with null cell controls, quantitative proteomics, in vivo model validation; single lab\",\n      \"pmids\": [\"40220918\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"NUFIP2 was identified as a TDP-43 interactor specifically associated with TDP-43 cytoplasmic mislocalization conditions (not under normal nuclear conditions). NUFIP2 sequesters TDP-43 into cytoplasmic aggregates and co-localizes with TDP-43 pathology in ALS/FTLD patient tissue.\",\n      \"method\": \"APEX2-driven proximity labeling, mass spectrometry, functional screen, immunofluorescence in patient tissue\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — proximity labeling with context-dependent conditions, functional validation in patient tissue; preprint, not yet peer-reviewed\",\n      \"pmids\": [\"40291645\"],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"O-GlcNAcylation of NUFIP2 regulates the formation of RNA-protein biocondensates (stress granules). Site mutagenesis and inhibition of O-GlcNAc transferase combined with fluorescence microscopy validated that O-GlcNAcylation promotes NUFIP2 condensate formation during stress recovery.\",\n      \"method\": \"Mass spectrometry-based chemoproteomics, site mutagenesis, O-GlcNAc transferase inhibition, fluorescence microscopy\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — site mutagenesis with functional condensate readout, OGT inhibition, imaging; single lab, NUFIP2 is one of several validated proteins\",\n      \"pmids\": [\"40307207\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"NUFIP2 is a multifunctional RNA-binding protein cofactor that interacts directly with FMRP (via FMRP's second Tudor repeat), serves as a cofactor for Roquin-induced mRNA decay by cooperatively binding non-canonical stem-loop structures in target 3'-UTRs (e.g., ICOS, Ox40), interacts with the RNA helicase DDX6, localizes to stress granules under cellular stress in a manner regulated by O-GlcNAcylation, is recruited to damaged lysosomes via direct GABARAP interaction to contribute to MTOR inactivation through the Ragulator-Rag complex, and interacts with ATXN2L and TDP-43 in contexts relevant to neurodegeneration.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"NUFIP2 is a multifunctional RNA-binding protein cofactor that operates at the interface of post-transcriptional regulation, stress-responsive ribonucleoprotein condensates, and lysosomal stress signaling [#0, #3, #6]. It was first defined as an FMRP-interacting protein (82-FIP) associated with polyribosomes within FMRP-containing mRNP complexes [#0], with structural work localizing the interaction to the second, flexible Tudor repeat of FMRP's N-terminal domain, whose fold also encodes a nucleolar localization signal that allosterically couples FMRP localization to its protein interactions [#1]. As a cofactor of Roquin-1/Roquin-2-induced mRNA decay, NUFIP2 binds Roquin directly and with high affinity and the two cooperatively recognize non-canonical stem-loop structures in target 3'-UTRs such as those of ICOS and Ox40 to drive post-transcriptional repression, with Roquin reciprocally stabilizing NUFIP2 in cells [#3]. NUFIP2 interacts RNA-independently with the helicase DDX6 and relocalizes to stress granules upon cellular stress, consistent with a role in translational repression [#2]; its incorporation into stress-granule condensates is promoted by O-GlcNAcylation during stress recovery [#9]. Distinct from its condensate function, NUFIP2 is recruited to damaged lysosomes through direct binding to GABARAP-family mATG8 proteins in an Atg8ylation-dependent manner, where it cooperates with galectin-8 to inactivate MTOR via the Ragulator-Rag complex [#6]. NUFIP2 is the primary interactor of ATXN2L and is depleted in ATXN2L-null cells, and it is captured into pathological aggregates with ATXN2 and with cytoplasmically mislocalized TDP-43 in neurodegeneration contexts [#7].\",\n  \"teleology\": [\n    {\n      \"year\": 2003,\n      \"claim\": \"Establishing what NUFIP2 does began with identifying its physical partner, defining it as an FMRP-associated, polyribosome-bound mRNP component rather than an orphan protein.\",\n      \"evidence\": \"Co-IP, yeast two-hybrid, subcellular fractionation, and immunofluorescence in cultured cells and neurons\",\n      \"pmids\": [\"12837692\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"RNA targets bound by NUFIP2 not defined\", \"functional consequence of the FMRP association on translation not established\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Structural definition of the FMRP N-terminal domain pinpointed the second Tudor repeat as the NUFIP2 contact and linked fold stability to FMRP localization, providing a molecular basis for the interaction.\",\n      \"evidence\": \"NMR structure determination with mutagenesis and localization assays\",\n      \"pmids\": [\"16407062\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"NUFIP2 region engaging the Tudor repeat not mapped\", \"functional output of the regulated interaction not resolved\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Linking NUFIP2 to a translational-repression machinery showed it binds DDX6 RNA-independently and partitions into stress granules, not P-bodies, under stress.\",\n      \"evidence\": \"RNA-independent Co-IP with mass spectrometry and immunofluorescence\",\n      \"pmids\": [\"26184334\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"functional role of the DDX6 interaction in repression not directly tested\", \"single-lab finding\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"An unbiased screen assigned NUFIP2 a defined post-transcriptional function as a Roquin cofactor that cooperatively recognizes non-canonical 3'-UTR stem-loops to drive mRNA decay.\",\n      \"evidence\": \"siRNA screen, direct binding and RNA EMSA, Co-IP, and reporter decay assays for ICOS/Ox40 elements\",\n      \"pmids\": [\"29352114\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"full set of NUFIP2-dependent Roquin targets unknown\", \"structural basis of cooperative RNA recognition not solved\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Co-IP placed NUFIP2 within a broader stress-granule protein network including ATXN2/ATXN2L and FAM98A.\",\n      \"evidence\": \"Co-immunoprecipitation (NUFIP2 a secondary finding)\",\n      \"pmids\": [\"29992460\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"single Co-IP without reciprocal validation\", \"direct versus indirect associations not distinguished\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Quantitative interactome mapping confirmed NUFIP2 as an N-terminal FMRP interactor embedded in RNA-metabolism and stress-granule networks.\",\n      \"evidence\": \"Affinity pull-down with quantitative LC-MS/MS and domain mapping\",\n      \"pmids\": [\"32525608\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"functional consequence of network membership not tested\", \"single-lab dataset\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"A new, condensate-independent role emerged: NUFIP2 is recruited to damaged lysosomes via direct GABARAP binding and contributes to MTOR inactivation through the Ragulator-Rag complex.\",\n      \"evidence\": \"LysoIP, proximity proteomics, Co-IP, and MTOR activity assays with Atg8ylation-dependence\",\n      \"pmids\": [\"36394332\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"how NUFIP2 mechanistically promotes MTOR inactivation at the lysosome unresolved\", \"relationship between RNA-binding activity and lysosomal function unclear\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"NUFIP2 was defined as the primary ATXN2L interactor whose levels depend on ATXN2L and which is sequestered as homodimers during pathological ATXN2 aggregation, connecting it to neurodegeneration.\",\n      \"evidence\": \"Reciprocal Co-IP in ATXN2L-null cells, proteome profiling, and SCA2 mouse spinal cord analysis\",\n      \"pmids\": [\"40220918\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"functional consequence of NUFIP2 sequestration on neuronal physiology not established\", \"single-lab\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Context-dependent proximity labeling identified NUFIP2 as a TDP-43 interactor that sequesters mislocalized TDP-43 into cytoplasmic aggregates seen in ALS/FTLD tissue.\",\n      \"evidence\": \"APEX2 proximity labeling, mass spectrometry, functional screen, and patient-tissue immunofluorescence (preprint)\",\n      \"pmids\": [\"40291645\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"not yet peer-reviewed\", \"directness of NUFIP2-TDP-43 interaction not established\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"A post-translational regulatory layer was added by showing O-GlcNAcylation of NUFIP2 promotes its incorporation into stress-granule biocondensates during stress recovery.\",\n      \"evidence\": \"Chemoproteomics, site mutagenesis, OGT inhibition, and fluorescence microscopy\",\n      \"pmids\": [\"40307207\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"modified residues' impact on RNA binding and Roquin/DDX6 functions not tested\", \"single-lab\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How NUFIP2's distinct activities — Roquin-dependent mRNA decay, stress-granule condensation, and lysosomal MTOR control — are integrated or switched within a cell remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"no unifying structural or regulatory model linking the functions\", \"intrinsic RNA-binding specificity of NUFIP2 alone not defined\", \"in vivo physiological role in immunity versus neurodegeneration not reconciled\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0003723\", \"supporting_discovery_ids\": [0, 3]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [3, 6]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [6]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [2]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [0]},\n      {\"term_id\": \"GO:0005764\", \"supporting_discovery_ids\": [6]},\n      {\"term_id\": \"GO:0005840\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-8953854\", \"supporting_discovery_ids\": [3]},\n      {\"term_id\": \"R-HSA-8953897\", \"supporting_discovery_ids\": [2, 9]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [6]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [3]}\n    ],\n    \"complexes\": [\"stress granule\"],\n    \"partners\": [\"FMRP\", \"DDX6\", \"RC3H1\", \"ATXN2L\", \"GABARAP\", \"TARDBP\", \"ATXN2\", \"FAM98A\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"faith_supported":6,"faith_total":6,"faith_pct":100.0}}