{"gene":"NUFIP1","run_date":"2026-04-29T11:37:57","timeline":{"discoveries":[{"year":2018,"finding":"NUFIP1 acts as a selective autophagy receptor (ribophagy receptor) that, upon mTORC1 inhibition/starvation, redistributes from the nucleus to autophagosomes and lysosomes, directly binds ribosomes, and delivers them to autophagosomes by directly binding LC3B; this ribophagy depends on NUFIP1's capacity to bind LC3B and promotes cell survival.","method":"Quantitative lysosome proteomics, subcellular fractionation, Co-IP, loss-of-function with cell survival readout, direct binding assays","journal":"Science","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal methods (proteomics, Co-IP, fractionation, functional rescue), high citation count, replicated in subsequent studies","pmids":["29700228"],"is_preprint":false},{"year":2003,"finding":"NUFIP1 is a nucleocytoplasmic shuttling protein that localizes to the nuclear matrix in RNA-containing structures, is present in the cytoplasm associated with ribosomes, and contains a functional CRM1-dependent nuclear export signal; in neurons it is detected in functional synaptoneurosomes co-localizing with ribosomes, suggesting a role in mRNA export/localization and local synaptic protein synthesis in association with FMRP.","method":"Subcellular fractionation, immunofluorescence, nuclear export signal mutagenesis, leptomycin B treatment, synaptoneurosomes isolation","journal":"Experimental cell research","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal methods (fractionation, imaging, mutagenesis, pharmacological inhibition) in a single rigorous study","pmids":["12941608"],"is_preprint":false},{"year":2004,"finding":"NUFIP interacts with BRCA1 and associates with the positive transcription elongation factor P-TEFb through its Cyclin T1 subunit; NUFIP stimulates activator-independent RNA polymerase II transcription in vitro and in vivo, is associated with preinitiation, open, and elongation complexes, and facilitates ATP-dependent dissociation of hyperphosphorylated pol II from open transcription complexes; mutation of its zinc-finger domain abolishes transcriptional activation.","method":"Yeast two-hybrid, immunodepletion, in vitro transcription assay, co-immunoprecipitation, zinc-finger domain mutagenesis","journal":"Oncogene","confidence":"High","confidence_rationale":"Tier 1–2 — in vitro reconstitution assay, immunodepletion rescue, mutagenesis, and Co-IP in single study","pmids":["15107825"],"is_preprint":false},{"year":2013,"finding":"NUFIP (human homolog of yeast Rsa1p) acts as an assembly scaffold for box C/D snoRNPs by binding the 15.5K protein (human homolog of yeast Snu13p); NMR structure and mutagenesis identified specific electrostatic and hydrophobic interface residues (R249, R246, K250 in Rsa1p; E72, D73 in Snu13p; W253 of Rsa1p inserted in hydrophobic cavity); this interaction is predicted to be mutually exclusive with active snoRNP assembly, suggesting NUFIP prevents premature snoRNP activity.","method":"NMR structure determination, mutagenesis, biophysical binding assays, yeast genetics (growth and snoRNP formation)","journal":"Nucleic acids research","confidence":"High","confidence_rationale":"Tier 1 — NMR structure with mutagenesis and in vivo functional validation","pmids":["24234454"],"is_preprint":false},{"year":2014,"finding":"The human ZNHIT3 (TRIP3) protein, showing sequence homology with yeast Hit1p, regulates the abundance of NUFIP1 (the human Rsa1p homolog); Hit1p/ZNHIT3 is required to maintain steady-state levels of Rsa1p/NUFIP1, and the Snu13p-Rsa1p-Hit1p heterotrimer can interact with C/D snoRNAs and the core protein Nop58.","method":"Proteomics, NMR structure of Rsa1p-Hit1p complex, biochemical reconstitution of heterotrimer, protein stability assays","journal":"Nucleic acids research","confidence":"High","confidence_rationale":"Tier 1 — NMR structure, reconstituted heterotrimer, functional stability data across species","pmids":["25170085"],"is_preprint":false},{"year":2019,"finding":"Under cyclic mechanical stress in trabecular meshwork cells, NUFIP1 translocates from the nucleus to LAMP2-positive lysosomal organelles and co-immunoprecipitates with nuclear LC3, suggesting a selective autophagy receptor role for a target other than ribosomes in this context; nuclear LC3 localizes to the nucleolus and interacts with NUFIP1 under mechanical stress.","method":"Biochemical fractionation, co-immunoprecipitation, live imaging (GFP-LC3/tfLC3), leptomycin B treatment, immunofluorescence","journal":"Autophagy","confidence":"Medium","confidence_rationale":"Tier 2–3 — Co-IP and localization with functional framing, single lab, the downstream selective autophagy target not identified","pmids":["31476975"],"is_preprint":false},{"year":2022,"finding":"In cancer-associated fibroblasts (CAFs), NUFIP1-dependent autophagy mediates secretion of nucleosides that support pancreatic tumor growth under glutamine deprivation; inhibiting NUFIP1 in the stroma reduced tumor weight in an orthotopic mouse model.","method":"NUFIP1 knockdown/loss-of-function, orthotopic mouse model, metabolic profiling, CAF-PDAC co-culture","journal":"Nature cancer","confidence":"Medium","confidence_rationale":"Tier 2 — clean KO with defined metabolic and tumor-growth phenotype, in vivo validation","pmids":["35982178"],"is_preprint":false},{"year":2025,"finding":"Phosphorylated NUFIP1 binds replication protein A2 (RPA32) to recruit the ATR-ATRIP complex, thereby triggering the DNA damage response (DDR); loss of NUFIP1 or its non-phosphorylatable mutant impairs the DDR under amino acid deficiency and induces necroptosis-related spontaneous enteritis in mice.","method":"Co-IP (phospho-NUFIP1 with RPA32/ATR-ATRIP), conditional knockout mouse model, phospho-mutant rescue experiments, in vitro DDR assays","journal":"Nature metabolism","confidence":"High","confidence_rationale":"Tier 2 — reciprocal Co-IP of phospho-NUFIP1 with DDR complex, phospho-mutant epistasis, conditional KO with defined phenotype","pmids":["39753713"],"is_preprint":false},{"year":2025,"finding":"Sepsis-induced ribosome collision activates the cGAS-STING signaling axis, which recruits NUFIP1 to STING protein complexes; NUFIP1-mediated ribophagy alleviates PANoptosis of CD4+ T lymphocytes via this cGAS-STING pathway, preserving immune function.","method":"NUFIP1 knockdown, CLP sepsis model, TMT proteomics, Co-IP (NUFIP1 with STING), cytokine assays, T cell proliferation","journal":"Research (Washington, D.C.)","confidence":"Medium","confidence_rationale":"Tier 2–3 — Co-IP and KD with defined immune phenotype, single lab, proteomic support","pmids":["40995563"],"is_preprint":false}],"current_model":"NUFIP1 is a multifunctional nuclear–cytoplasmic shuttling protein that acts as a selective autophagy (ribophagy) receptor by binding ribosomes and LC3B to deliver ribosomes to autophagosomes upon mTORC1 inhibition; serves as a scaffold for box C/D snoRNP assembly by bridging 15.5K/Snu13p and the R2TP chaperone complex while preventing premature snoRNP activity; associates with BRCA1 and P-TEFb to stimulate RNA polymerase II transcription; and in the DNA damage response, phosphorylated NUFIP1 binds RPA32 to recruit the ATR-ATRIP complex, linking nutrient sensing to genome integrity and intestinal homeostasis."},"narrative":{"teleology":[{"year":2003,"claim":"Establishing that NUFIP1 is not a purely nuclear protein but a CRM1-dependent nucleocytoplasmic shuttle associated with ribosomes in both the cytoplasm and synaptoneurosomes provided the first framework for understanding its dual nuclear and cytoplasmic roles.","evidence":"Subcellular fractionation, immunofluorescence, nuclear export signal mutagenesis, and leptomycin B treatment in neuronal and non-neuronal cells","pmids":["12941608"],"confidence":"High","gaps":["Direct RNA or ribosome-binding domains were not mapped","Functional consequence of ribosome association in the cytoplasm was not tested"]},{"year":2004,"claim":"Demonstrating that NUFIP1 associates with BRCA1 and P-TEFb (Cyclin T1) and stimulates RNA Pol II transcription in a zinc-finger-dependent manner revealed an unexpected transcriptional co-activator function.","evidence":"Yeast two-hybrid, Co-IP, in vitro transcription with immunodepletion/rescue, zinc-finger mutagenesis","pmids":["15107825"],"confidence":"High","gaps":["Endogenous target genes regulated by NUFIP1's transcriptional activity were not identified","Relationship between transcriptional and snoRNP/ribophagy functions was not addressed"]},{"year":2013,"claim":"Solving the NMR structure of the NUFIP1/Rsa1p–15.5K/Snu13p interface and showing mutual exclusivity with active snoRNP assembly established NUFIP1 as a quality-control scaffold that prevents premature snoRNP function.","evidence":"NMR structure determination, mutagenesis of interface residues, yeast genetics assessing snoRNP formation","pmids":["24234454"],"confidence":"High","gaps":["Mechanism by which NUFIP1 is released upon completed snoRNP assembly was not defined","Whether NUFIP1 scaffolding extends to box H/ACA snoRNPs was not tested"]},{"year":2014,"claim":"Identifying ZNHIT3/Hit1p as a stabilizer of NUFIP1/Rsa1p and reconstituting a Snu13p–Rsa1p–Hit1p heterotrimer that binds C/D snoRNAs and Nop58 clarified the minimal assembly platform for snoRNP biogenesis.","evidence":"NMR structure of Rsa1p–Hit1p complex, biochemical reconstitution, protein stability assays across yeast and human","pmids":["25170085"],"confidence":"High","gaps":["How the heterotrimer hands off the snoRNA to the mature snoRNP particle was not resolved","In vivo stoichiometry and dynamics of the complex were not measured"]},{"year":2018,"claim":"The key conceptual advance was identifying NUFIP1 as a selective autophagy receptor for ribosomes: upon mTORC1 inhibition it relocates to autophagosomes, directly binds both ribosomes and LC3B, and promotes ribophagy-dependent cell survival.","evidence":"Quantitative lysosome proteomics, subcellular fractionation, Co-IP, direct binding assays, and loss-of-function survival assays in mammalian cells","pmids":["29700228"],"confidence":"High","gaps":["Structural basis for NUFIP1–ribosome recognition was not determined","Whether NUFIP1 distinguishes 40S from 60S subunits or targets specific ribosome populations was unclear"]},{"year":2019,"claim":"Observation that mechanical stress triggers NUFIP1 translocation to lysosomes and its interaction with nuclear LC3 in trabecular meshwork cells extended the autophagy receptor concept beyond nutrient deprivation, although the cargo in this context was not identified.","evidence":"Co-IP, live imaging of GFP-LC3, biochemical fractionation under cyclic mechanical stress","pmids":["31476975"],"confidence":"Medium","gaps":["The specific autophagy cargo targeted by NUFIP1 under mechanical stress was not identified","Whether ribosome degradation occurs in this context was not tested"]},{"year":2022,"claim":"Showing that NUFIP1-dependent ribophagy in cancer-associated fibroblasts supplies nucleosides that fuel pancreatic tumor growth connected the ribophagy receptor function to a tumor-promoting metabolic pathway in vivo.","evidence":"NUFIP1 knockdown in CAFs, orthotopic PDAC mouse model, metabolic profiling, co-culture assays","pmids":["35982178"],"confidence":"Medium","gaps":["Whether tumor cells also utilize intrinsic NUFIP1-mediated ribophagy for survival was not distinguished","Specificity of nucleoside supply versus other autophagy-derived metabolites was not fully resolved"]},{"year":2025,"claim":"Two studies expanded NUFIP1's mechanistic repertoire: phospho-NUFIP1 recruits ATR-ATRIP via RPA32 to activate the DNA damage response under amino acid deficiency (with conditional knockout causing necroptosis-driven enteritis), and separately NUFIP1-mediated ribophagy alleviates sepsis-induced PANoptosis of CD4+ T cells via the cGAS-STING axis.","evidence":"Co-IP of phospho-NUFIP1 with RPA32/ATR-ATRIP, phospho-mutant rescue, conditional KO mouse enteritis model (DDR study); Co-IP of NUFIP1 with STING, CLP sepsis model, TMT proteomics (sepsis study)","pmids":["39753713","40995563"],"confidence":"High","gaps":["The kinase responsible for NUFIP1 phosphorylation upstream of DDR activation was not identified","Whether the DDR and ribophagy functions of NUFIP1 are coordinated or mutually exclusive under nutrient stress was not resolved","The NUFIP1–STING interaction in sepsis was shown by single-lab Co-IP and awaits independent confirmation"]},{"year":null,"claim":"How NUFIP1 toggles between its distinct roles — snoRNP assembly scaffold, ribophagy receptor, transcriptional co-activator, and DDR adaptor — depending on cellular context remains an open question; the regulatory switches (post-translational modifications, competitive binding) that partition NUFIP1 among these functions are not understood.","evidence":"","pmids":[],"confidence":"Low","gaps":["No integrated model explains how NUFIP1 is partitioned among its four known functions","Structural basis for NUFIP1–ribosome and NUFIP1–LC3B interaction has not been determined","Whether loss of NUFIP1 in humans causes a Mendelian phenotype is unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[0,3,4,7]},{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[2]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[1,2,3]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[1]},{"term_id":"GO:0005764","term_label":"lysosome","supporting_discovery_ids":[0,5]},{"term_id":"GO:0031410","term_label":"cytoplasmic vesicle","supporting_discovery_ids":[0]}],"pathway":[{"term_id":"R-HSA-9612973","term_label":"Autophagy","supporting_discovery_ids":[0,5,6,8]},{"term_id":"R-HSA-73894","term_label":"DNA Repair","supporting_discovery_ids":[7]},{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[2]},{"term_id":"R-HSA-8953854","term_label":"Metabolism of RNA","supporting_discovery_ids":[3,4]}],"complexes":["Snu13/15.5K-NUFIP1-ZNHIT3 snoRNP assembly platform"],"partners":["NHPX","ZNHIT3","BRCA1","CCNT1","MAP1LC3B","RPA2","STING1"],"other_free_text":[]},"mechanistic_narrative":"NUFIP1 is a nucleocytoplasmic shuttling protein that functions as a selective autophagy (ribophagy) receptor, a scaffold for box C/D snoRNP assembly, and a participant in transcription and the DNA damage response. Upon mTORC1 inhibition or nutrient stress, NUFIP1 redistributes from the nucleus to autophagosomes, directly binds ribosomes and LC3B, and delivers ribosomes for lysosomal degradation, promoting cell survival and supplying nucleosides to neighboring cells [PMID:29700228, PMID:35982178]. NUFIP1 bridges the 15.5K/Snu13p snoRNP core protein and the R2TP chaperone via a structurally characterized interface stabilized by ZNHIT3, preventing premature snoRNP activity during assembly [PMID:24234454, PMID:25170085]. Phosphorylated NUFIP1 also binds RPA32 to recruit ATR-ATRIP, activating the DNA damage response under amino acid deficiency; loss of this function causes necroptosis-driven spontaneous enteritis in mice [PMID:39753713]."},"prefetch_data":{"uniprot":{"accession":"Q9UHK0","full_name":"FMR1-interacting protein NUFIP1","aliases":["Nuclear FMR1-interacting protein 1","Nuclear FMRP-interacting protein 1"],"length_aa":495,"mass_kda":56.3,"function":"Binds RNA","subcellular_location":"Nucleus","url":"https://www.uniprot.org/uniprotkb/Q9UHK0/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":true,"resolved_as":"","url":"https://depmap.org/portal/gene/NUFIP1","classification":"Common Essential","n_dependent_lines":925,"n_total_lines":1208,"dependency_fraction":0.765728476821192},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"NOP58","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/NUFIP1","total_profiled":1310},"omim":[{"mim_id":"613884","title":"CHROMOSOME 13q14 DELETION SYNDROME","url":"https://www.omim.org/entry/613884"},{"mim_id":"611281","title":"KELCH DOMAIN-CONTAINING PROTEIN 1; KLHDC1","url":"https://www.omim.org/entry/611281"},{"mim_id":"609356","title":"NUCLEAR FMRP-INTERACTING PROTEIN 2; NUFIP2","url":"https://www.omim.org/entry/609356"},{"mim_id":"604354","title":"NUCLEAR FMRP-INTERACTING PROTEIN 1; NUFIP1","url":"https://www.omim.org/entry/604354"},{"mim_id":"309550","title":"FRAGILE X MESSENGER RIBONUCLEOPROTEIN 1; FMR1","url":"https://www.omim.org/entry/309550"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Enhanced","locations":[{"location":"Nucleoplasm","reliability":"Enhanced"},{"location":"Nucleoli","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/NUFIP1"},"hgnc":{"alias_symbol":["NUFIP","Rsa1"],"prev_symbol":[]},"alphafold":{"accession":"Q9UHK0","domains":[{"cath_id":"-","chopping":"170-228","consensus_level":"medium","plddt":83.7566,"start":170,"end":228},{"cath_id":"-","chopping":"230-271_464-473","consensus_level":"medium","plddt":84.306,"start":230,"end":473}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9UHK0","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9UHK0-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9UHK0-F1-predicted_aligned_error_v6.png","plddt_mean":55.25},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=NUFIP1","jax_strain_url":"https://www.jax.org/strain/search?query=NUFIP1"},"sequence":{"accession":"Q9UHK0","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9UHK0.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9UHK0/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9UHK0"}},"corpus_meta":[{"pmid":"29700228","id":"PMC_29700228","title":"NUFIP1 is a ribosome receptor for starvation-induced ribophagy.","date":"2018","source":"Science (New York, N.Y.)","url":"https://pubmed.ncbi.nlm.nih.gov/29700228","citation_count":290,"is_preprint":false},{"pmid":"35982178","id":"PMC_35982178","title":"Cancer-associated fibroblasts employ NUFIP1-dependent autophagy to secrete nucleosides and support pancreatic tumor growth.","date":"2022","source":"Nature cancer","url":"https://pubmed.ncbi.nlm.nih.gov/35982178","citation_count":75,"is_preprint":false},{"pmid":"31476975","id":"PMC_31476975","title":"The autophagic protein LC3 translocates to the nucleus and localizes in the nucleolus associated to NUFIP1 in response to cyclic mechanical stress.","date":"2019","source":"Autophagy","url":"https://pubmed.ncbi.nlm.nih.gov/31476975","citation_count":56,"is_preprint":false},{"pmid":"12941608","id":"PMC_12941608","title":"NUFIP1 (nuclear FMRP interacting protein 1) is a nucleocytoplasmic shuttling protein associated with active synaptoneurosomes.","date":"2003","source":"Experimental cell research","url":"https://pubmed.ncbi.nlm.nih.gov/12941608","citation_count":46,"is_preprint":false},{"pmid":"25170085","id":"PMC_25170085","title":"Protein Hit1, a novel box C/D snoRNP assembly factor, controls cellular concentration of the scaffolding protein Rsa1 by direct interaction.","date":"2014","source":"Nucleic acids research","url":"https://pubmed.ncbi.nlm.nih.gov/25170085","citation_count":44,"is_preprint":false},{"pmid":"3001646","id":"PMC_3001646","title":"Rsa1 polymorphism at the insulin receptor locus (INSR) on chromosome 19.","date":"1985","source":"Nucleic acids research","url":"https://pubmed.ncbi.nlm.nih.gov/3001646","citation_count":33,"is_preprint":false},{"pmid":"24234454","id":"PMC_24234454","title":"Characterization of the interaction between protein Snu13p/15.5K and the Rsa1p/NUFIP factor and demonstration of its functional importance for snoRNP assembly.","date":"2013","source":"Nucleic acids research","url":"https://pubmed.ncbi.nlm.nih.gov/24234454","citation_count":33,"is_preprint":false},{"pmid":"31861284","id":"PMC_31861284","title":"Thrombolytic Potential of Novel Thiol-Dependent Fibrinolytic Protease from Bacillus cereus RSA1.","date":"2019","source":"Biomolecules","url":"https://pubmed.ncbi.nlm.nih.gov/31861284","citation_count":27,"is_preprint":false},{"pmid":"15107825","id":"PMC_15107825","title":"BRCA1 cooperates with NUFIP and P-TEFb to activate transcription by RNA polymerase II.","date":"2004","source":"Oncogene","url":"https://pubmed.ncbi.nlm.nih.gov/15107825","citation_count":26,"is_preprint":false},{"pmid":"7139016","id":"PMC_7139016","title":"Purification of rabbit sperm autoantigens by preparative SDS gel electrophoresis: amino acid and carbohydrate content of RSA-1.","date":"1982","source":"Biology of reproduction","url":"https://pubmed.ncbi.nlm.nih.gov/7139016","citation_count":26,"is_preprint":false},{"pmid":"34141495","id":"PMC_34141495","title":"Computational-approach understanding the structure-function prophecy of Fibrinolytic Protease RFEA1 from Bacillus cereus RSA1.","date":"2021","source":"PeerJ","url":"https://pubmed.ncbi.nlm.nih.gov/34141495","citation_count":14,"is_preprint":false},{"pmid":"39753713","id":"PMC_39753713","title":"NUFIP1 integrates amino acid sensing and DNA damage response to maintain the intestinal homeostasis.","date":"2025","source":"Nature metabolism","url":"https://pubmed.ncbi.nlm.nih.gov/39753713","citation_count":13,"is_preprint":false},{"pmid":"40995563","id":"PMC_40995563","title":"NUFIP1-Mediated Ribophagy Alleviates PANoptosis of CD4+ T Lymphocytes in Sepsis via the cGAS-STING Pathway.","date":"2025","source":"Research (Washington, D.C.)","url":"https://pubmed.ncbi.nlm.nih.gov/40995563","citation_count":9,"is_preprint":false},{"pmid":"38599287","id":"PMC_38599287","title":"NUFIP1-engineered exosomes derived from hUMSCs regulate apoptosis and neurological injury induced by propofol in newborn rats.","date":"2024","source":"Neurotoxicology","url":"https://pubmed.ncbi.nlm.nih.gov/38599287","citation_count":5,"is_preprint":false},{"pmid":"34367967","id":"PMC_34367967","title":"Targeting NUFIP1 Suppresses Growth and Induces Senescence of Colorectal Cancer Cells.","date":"2021","source":"Frontiers in oncology","url":"https://pubmed.ncbi.nlm.nih.gov/34367967","citation_count":4,"is_preprint":false},{"pmid":"34681713","id":"PMC_34681713","title":"High Resolution Structure of the Mature Capsid of Ralstonia solanacearum Bacteriophage ϕRSA1 by Cryo-Electron Microscopy.","date":"2021","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/34681713","citation_count":3,"is_preprint":false},{"pmid":"41366789","id":"PMC_41366789","title":"NUFIP1 at the crossroads of ribophagy and disease: unveiling therapeutic implications.","date":"2025","source":"Journal of translational medicine","url":"https://pubmed.ncbi.nlm.nih.gov/41366789","citation_count":0,"is_preprint":false},{"pmid":"41942784","id":"PMC_41942784","title":"NUFIP1-engineered exosomes modulate propofol-induced neurotoxicity in neonatal rats via the ERS apoptotic pathway.","date":"2026","source":"Apoptosis : an international journal on programmed cell death","url":"https://pubmed.ncbi.nlm.nih.gov/41942784","citation_count":0,"is_preprint":false},{"pmid":"41783044","id":"PMC_41783044","title":"Erratum to \"NUFIP1-Mediated Ribophagy Alleviates PANoptosis of CD4+ T Lymphocytes in Sepsis via the cGAS-STING Pathway\".","date":"2026","source":"Research (Washington, D.C.)","url":"https://pubmed.ncbi.nlm.nih.gov/41783044","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2024.12.19.629410","title":"Genome-wide association analyses in dairy heifers highlight genes overlapping with mouse and human fertility and human health traits","date":"2024-12-21","source":"bioRxiv","url":"https://doi.org/10.1101/2024.12.19.629410","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":11607,"output_tokens":2460,"usd":0.03586},"stage2":{"model":"claude-opus-4-6","input_tokens":5759,"output_tokens":2711,"usd":0.144855},"total_usd":0.180715,"stage1_batch_id":"msgbatch_012ZiiCUBfB62NCTQd4Bk1Jo","stage2_batch_id":"msgbatch_01Xuqq9aUHoQouS7UVGZNStZ","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2018,\n      \"finding\": \"NUFIP1 acts as a selective autophagy receptor (ribophagy receptor) that, upon mTORC1 inhibition/starvation, redistributes from the nucleus to autophagosomes and lysosomes, directly binds ribosomes, and delivers them to autophagosomes by directly binding LC3B; this ribophagy depends on NUFIP1's capacity to bind LC3B and promotes cell survival.\",\n      \"method\": \"Quantitative lysosome proteomics, subcellular fractionation, Co-IP, loss-of-function with cell survival readout, direct binding assays\",\n      \"journal\": \"Science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods (proteomics, Co-IP, fractionation, functional rescue), high citation count, replicated in subsequent studies\",\n      \"pmids\": [\"29700228\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"NUFIP1 is a nucleocytoplasmic shuttling protein that localizes to the nuclear matrix in RNA-containing structures, is present in the cytoplasm associated with ribosomes, and contains a functional CRM1-dependent nuclear export signal; in neurons it is detected in functional synaptoneurosomes co-localizing with ribosomes, suggesting a role in mRNA export/localization and local synaptic protein synthesis in association with FMRP.\",\n      \"method\": \"Subcellular fractionation, immunofluorescence, nuclear export signal mutagenesis, leptomycin B treatment, synaptoneurosomes isolation\",\n      \"journal\": \"Experimental cell research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods (fractionation, imaging, mutagenesis, pharmacological inhibition) in a single rigorous study\",\n      \"pmids\": [\"12941608\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"NUFIP interacts with BRCA1 and associates with the positive transcription elongation factor P-TEFb through its Cyclin T1 subunit; NUFIP stimulates activator-independent RNA polymerase II transcription in vitro and in vivo, is associated with preinitiation, open, and elongation complexes, and facilitates ATP-dependent dissociation of hyperphosphorylated pol II from open transcription complexes; mutation of its zinc-finger domain abolishes transcriptional activation.\",\n      \"method\": \"Yeast two-hybrid, immunodepletion, in vitro transcription assay, co-immunoprecipitation, zinc-finger domain mutagenesis\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — in vitro reconstitution assay, immunodepletion rescue, mutagenesis, and Co-IP in single study\",\n      \"pmids\": [\"15107825\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"NUFIP (human homolog of yeast Rsa1p) acts as an assembly scaffold for box C/D snoRNPs by binding the 15.5K protein (human homolog of yeast Snu13p); NMR structure and mutagenesis identified specific electrostatic and hydrophobic interface residues (R249, R246, K250 in Rsa1p; E72, D73 in Snu13p; W253 of Rsa1p inserted in hydrophobic cavity); this interaction is predicted to be mutually exclusive with active snoRNP assembly, suggesting NUFIP prevents premature snoRNP activity.\",\n      \"method\": \"NMR structure determination, mutagenesis, biophysical binding assays, yeast genetics (growth and snoRNP formation)\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — NMR structure with mutagenesis and in vivo functional validation\",\n      \"pmids\": [\"24234454\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"The human ZNHIT3 (TRIP3) protein, showing sequence homology with yeast Hit1p, regulates the abundance of NUFIP1 (the human Rsa1p homolog); Hit1p/ZNHIT3 is required to maintain steady-state levels of Rsa1p/NUFIP1, and the Snu13p-Rsa1p-Hit1p heterotrimer can interact with C/D snoRNAs and the core protein Nop58.\",\n      \"method\": \"Proteomics, NMR structure of Rsa1p-Hit1p complex, biochemical reconstitution of heterotrimer, protein stability assays\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — NMR structure, reconstituted heterotrimer, functional stability data across species\",\n      \"pmids\": [\"25170085\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Under cyclic mechanical stress in trabecular meshwork cells, NUFIP1 translocates from the nucleus to LAMP2-positive lysosomal organelles and co-immunoprecipitates with nuclear LC3, suggesting a selective autophagy receptor role for a target other than ribosomes in this context; nuclear LC3 localizes to the nucleolus and interacts with NUFIP1 under mechanical stress.\",\n      \"method\": \"Biochemical fractionation, co-immunoprecipitation, live imaging (GFP-LC3/tfLC3), leptomycin B treatment, immunofluorescence\",\n      \"journal\": \"Autophagy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 — Co-IP and localization with functional framing, single lab, the downstream selective autophagy target not identified\",\n      \"pmids\": [\"31476975\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"In cancer-associated fibroblasts (CAFs), NUFIP1-dependent autophagy mediates secretion of nucleosides that support pancreatic tumor growth under glutamine deprivation; inhibiting NUFIP1 in the stroma reduced tumor weight in an orthotopic mouse model.\",\n      \"method\": \"NUFIP1 knockdown/loss-of-function, orthotopic mouse model, metabolic profiling, CAF-PDAC co-culture\",\n      \"journal\": \"Nature cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — clean KO with defined metabolic and tumor-growth phenotype, in vivo validation\",\n      \"pmids\": [\"35982178\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Phosphorylated NUFIP1 binds replication protein A2 (RPA32) to recruit the ATR-ATRIP complex, thereby triggering the DNA damage response (DDR); loss of NUFIP1 or its non-phosphorylatable mutant impairs the DDR under amino acid deficiency and induces necroptosis-related spontaneous enteritis in mice.\",\n      \"method\": \"Co-IP (phospho-NUFIP1 with RPA32/ATR-ATRIP), conditional knockout mouse model, phospho-mutant rescue experiments, in vitro DDR assays\",\n      \"journal\": \"Nature metabolism\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal Co-IP of phospho-NUFIP1 with DDR complex, phospho-mutant epistasis, conditional KO with defined phenotype\",\n      \"pmids\": [\"39753713\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Sepsis-induced ribosome collision activates the cGAS-STING signaling axis, which recruits NUFIP1 to STING protein complexes; NUFIP1-mediated ribophagy alleviates PANoptosis of CD4+ T lymphocytes via this cGAS-STING pathway, preserving immune function.\",\n      \"method\": \"NUFIP1 knockdown, CLP sepsis model, TMT proteomics, Co-IP (NUFIP1 with STING), cytokine assays, T cell proliferation\",\n      \"journal\": \"Research (Washington, D.C.)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 — Co-IP and KD with defined immune phenotype, single lab, proteomic support\",\n      \"pmids\": [\"40995563\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"NUFIP1 is a multifunctional nuclear–cytoplasmic shuttling protein that acts as a selective autophagy (ribophagy) receptor by binding ribosomes and LC3B to deliver ribosomes to autophagosomes upon mTORC1 inhibition; serves as a scaffold for box C/D snoRNP assembly by bridging 15.5K/Snu13p and the R2TP chaperone complex while preventing premature snoRNP activity; associates with BRCA1 and P-TEFb to stimulate RNA polymerase II transcription; and in the DNA damage response, phosphorylated NUFIP1 binds RPA32 to recruit the ATR-ATRIP complex, linking nutrient sensing to genome integrity and intestinal homeostasis.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"NUFIP1 is a nucleocytoplasmic shuttling protein that functions as a selective autophagy (ribophagy) receptor, a scaffold for box C/D snoRNP assembly, and a participant in transcription and the DNA damage response. Upon mTORC1 inhibition or nutrient stress, NUFIP1 redistributes from the nucleus to autophagosomes, directly binds ribosomes and LC3B, and delivers ribosomes for lysosomal degradation, promoting cell survival and supplying nucleosides to neighboring cells [PMID:29700228, PMID:35982178]. NUFIP1 bridges the 15.5K/Snu13p snoRNP core protein and the R2TP chaperone via a structurally characterized interface stabilized by ZNHIT3, preventing premature snoRNP activity during assembly [PMID:24234454, PMID:25170085]. Phosphorylated NUFIP1 also binds RPA32 to recruit ATR-ATRIP, activating the DNA damage response under amino acid deficiency; loss of this function causes necroptosis-driven spontaneous enteritis in mice [PMID:39753713].\",\n  \"teleology\": [\n    {\n      \"year\": 2003,\n      \"claim\": \"Establishing that NUFIP1 is not a purely nuclear protein but a CRM1-dependent nucleocytoplasmic shuttle associated with ribosomes in both the cytoplasm and synaptoneurosomes provided the first framework for understanding its dual nuclear and cytoplasmic roles.\",\n      \"evidence\": \"Subcellular fractionation, immunofluorescence, nuclear export signal mutagenesis, and leptomycin B treatment in neuronal and non-neuronal cells\",\n      \"pmids\": [\"12941608\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Direct RNA or ribosome-binding domains were not mapped\",\n        \"Functional consequence of ribosome association in the cytoplasm was not tested\"\n      ]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Demonstrating that NUFIP1 associates with BRCA1 and P-TEFb (Cyclin T1) and stimulates RNA Pol II transcription in a zinc-finger-dependent manner revealed an unexpected transcriptional co-activator function.\",\n      \"evidence\": \"Yeast two-hybrid, Co-IP, in vitro transcription with immunodepletion/rescue, zinc-finger mutagenesis\",\n      \"pmids\": [\"15107825\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Endogenous target genes regulated by NUFIP1's transcriptional activity were not identified\",\n        \"Relationship between transcriptional and snoRNP/ribophagy functions was not addressed\"\n      ]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Solving the NMR structure of the NUFIP1/Rsa1p–15.5K/Snu13p interface and showing mutual exclusivity with active snoRNP assembly established NUFIP1 as a quality-control scaffold that prevents premature snoRNP function.\",\n      \"evidence\": \"NMR structure determination, mutagenesis of interface residues, yeast genetics assessing snoRNP formation\",\n      \"pmids\": [\"24234454\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Mechanism by which NUFIP1 is released upon completed snoRNP assembly was not defined\",\n        \"Whether NUFIP1 scaffolding extends to box H/ACA snoRNPs was not tested\"\n      ]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Identifying ZNHIT3/Hit1p as a stabilizer of NUFIP1/Rsa1p and reconstituting a Snu13p–Rsa1p–Hit1p heterotrimer that binds C/D snoRNAs and Nop58 clarified the minimal assembly platform for snoRNP biogenesis.\",\n      \"evidence\": \"NMR structure of Rsa1p–Hit1p complex, biochemical reconstitution, protein stability assays across yeast and human\",\n      \"pmids\": [\"25170085\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"How the heterotrimer hands off the snoRNA to the mature snoRNP particle was not resolved\",\n        \"In vivo stoichiometry and dynamics of the complex were not measured\"\n      ]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"The key conceptual advance was identifying NUFIP1 as a selective autophagy receptor for ribosomes: upon mTORC1 inhibition it relocates to autophagosomes, directly binds both ribosomes and LC3B, and promotes ribophagy-dependent cell survival.\",\n      \"evidence\": \"Quantitative lysosome proteomics, subcellular fractionation, Co-IP, direct binding assays, and loss-of-function survival assays in mammalian cells\",\n      \"pmids\": [\"29700228\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Structural basis for NUFIP1–ribosome recognition was not determined\",\n        \"Whether NUFIP1 distinguishes 40S from 60S subunits or targets specific ribosome populations was unclear\"\n      ]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Observation that mechanical stress triggers NUFIP1 translocation to lysosomes and its interaction with nuclear LC3 in trabecular meshwork cells extended the autophagy receptor concept beyond nutrient deprivation, although the cargo in this context was not identified.\",\n      \"evidence\": \"Co-IP, live imaging of GFP-LC3, biochemical fractionation under cyclic mechanical stress\",\n      \"pmids\": [\"31476975\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"The specific autophagy cargo targeted by NUFIP1 under mechanical stress was not identified\",\n        \"Whether ribosome degradation occurs in this context was not tested\"\n      ]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Showing that NUFIP1-dependent ribophagy in cancer-associated fibroblasts supplies nucleosides that fuel pancreatic tumor growth connected the ribophagy receptor function to a tumor-promoting metabolic pathway in vivo.\",\n      \"evidence\": \"NUFIP1 knockdown in CAFs, orthotopic PDAC mouse model, metabolic profiling, co-culture assays\",\n      \"pmids\": [\"35982178\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Whether tumor cells also utilize intrinsic NUFIP1-mediated ribophagy for survival was not distinguished\",\n        \"Specificity of nucleoside supply versus other autophagy-derived metabolites was not fully resolved\"\n      ]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Two studies expanded NUFIP1's mechanistic repertoire: phospho-NUFIP1 recruits ATR-ATRIP via RPA32 to activate the DNA damage response under amino acid deficiency (with conditional knockout causing necroptosis-driven enteritis), and separately NUFIP1-mediated ribophagy alleviates sepsis-induced PANoptosis of CD4+ T cells via the cGAS-STING axis.\",\n      \"evidence\": \"Co-IP of phospho-NUFIP1 with RPA32/ATR-ATRIP, phospho-mutant rescue, conditional KO mouse enteritis model (DDR study); Co-IP of NUFIP1 with STING, CLP sepsis model, TMT proteomics (sepsis study)\",\n      \"pmids\": [\"39753713\", \"40995563\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"The kinase responsible for NUFIP1 phosphorylation upstream of DDR activation was not identified\",\n        \"Whether the DDR and ribophagy functions of NUFIP1 are coordinated or mutually exclusive under nutrient stress was not resolved\",\n        \"The NUFIP1–STING interaction in sepsis was shown by single-lab Co-IP and awaits independent confirmation\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How NUFIP1 toggles between its distinct roles — snoRNP assembly scaffold, ribophagy receptor, transcriptional co-activator, and DDR adaptor — depending on cellular context remains an open question; the regulatory switches (post-translational modifications, competitive binding) that partition NUFIP1 among these functions are not understood.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"No integrated model explains how NUFIP1 is partitioned among its four known functions\",\n        \"Structural basis for NUFIP1–ribosome and NUFIP1–LC3B interaction has not been determined\",\n        \"Whether loss of NUFIP1 in humans causes a Mendelian phenotype is unknown\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [0, 3, 4, 7]},\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [2]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [1, 2, 3]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [1]},\n      {\"term_id\": \"GO:0005764\", \"supporting_discovery_ids\": [0, 5]},\n      {\"term_id\": \"GO:0031410\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-9612973\", \"supporting_discovery_ids\": [0, 5, 6, 8]},\n      {\"term_id\": \"R-HSA-73894\", \"supporting_discovery_ids\": [7]},\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [2]},\n      {\"term_id\": \"R-HSA-8953854\", \"supporting_discovery_ids\": [3, 4]}\n    ],\n    \"complexes\": [\n      \"Snu13/15.5K-NUFIP1-ZNHIT3 snoRNP assembly platform\"\n    ],\n    \"partners\": [\n      \"NHPX\",\n      \"ZNHIT3\",\n      \"BRCA1\",\n      \"CCNT1\",\n      \"MAP1LC3B\",\n      \"RPA2\",\n      \"STING1\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}