{"gene":"NUFIP1","run_date":"2026-06-10T05:19:52","timeline":{"discoveries":[{"year":2018,"finding":"Upon mTORC1 inhibition or nutrient starvation, NUFIP1 redistributes from the nucleus to autophagosomes and lysosomes, where it directly binds LC3B to deliver ribosomes to autophagosomes, functioning as a selective autophagy receptor (ribophagy receptor). This starvation-induced ribophagy depends on the capacity of NUFIP1 to bind LC3B and promotes cell survival.","method":"Quantitative lysosome proteomics, co-immunoprecipitation (NUFIP1-LC3B interaction), subcellular fractionation/imaging, loss-of-function (NUFIP1 knockdown with cell survival readout), mTORC1 inhibition experiments","journal":"Science","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (proteomics, Co-IP, imaging, functional KD with survival readout), highly cited, single rigorous study with strong mechanistic validation","pmids":["29700228"],"is_preprint":false},{"year":2003,"finding":"NUFIP1 is a nucleocytoplasmic shuttling protein: it localizes in the nuclear matrix in RNA-containing structures, is also present in the cytoplasm associated with ribosomes, and is detected in functional synaptoneurosomes in neurons where it co-localizes with ribosomes. NUFIP1 contains a functional CRM1-dependent nuclear export signal mediating its shuttling between nucleus and cytoplasm.","method":"Subcellular fractionation, immunofluorescence imaging, synaptosome isolation and immunodetection, leptomycin B (CRM1 inhibitor) treatment demonstrating nuclear export signal function","journal":"Experimental cell research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct localization experiments with functional consequence (CRM1-dependent export), single lab, multiple orthogonal methods","pmids":["12941608"],"is_preprint":false},{"year":2013,"finding":"NUFIP1 (the human homolog of yeast Rsa1p) acts as a scaffold/assembly factor for box C/D snoRNPs by directly interacting with the RNA-binding core protein 15.5K (human homolog of yeast Snu13p). NMR structure determination and docking identified the interface: residues R249, R246, K250 of Rsa1p and E72, D73 of Snu13p form electrostatic interactions, with W253 of Rsa1p inserted in a hydrophobic cavity of Snu13p. This interaction is predicted to be exclusive of interactions in active snoRNPs, suggesting Rsa1p/NUFIP1 prevents premature snoRNP activity.","method":"NMR structure determination, biophysical interaction assays, site-directed mutagenesis in yeast (cell growth and snoRNP formation readouts), molecular docking","journal":"Nucleic acids research","confidence":"High","confidence_rationale":"Tier 1 / Strong — NMR structure plus mutagenesis plus functional validation in yeast, multiple orthogonal methods in one rigorous study","pmids":["24234454"],"is_preprint":false},{"year":2014,"finding":"NUFIP1 (human functional homolog of yeast Rsa1p) interacts with ZNHIT3 (TRIP3, human homolog of yeast Hit1p), which stabilizes NUFIP1 protein levels. The yeast Rsa1p-Hit1p complex structure was determined by NMR, revealing a novel mode of protein-protein association. The purified Snu13p-Rsa1p-Hit1p heterotrimer can interact with C/D snoRNAs and core protein Nop58, placing NUFIP1 within the snoRNP assembly pathway.","method":"Proteomic (pulldown/MS), NMR structure determination of yeast Rsa1p-Hit1p complex, functional studies (C/D snoRNA stability, pre-RNA maturation), in vitro binding with purified heterotrimer, demonstration that human ZNHIT3 regulates NUFIP1 abundance","journal":"Nucleic acids research","confidence":"High","confidence_rationale":"Tier 1 / Strong — NMR structure of the complex, reconstituted heterotrimer binding, functional readouts, with human NUFIP1 regulatory finding included","pmids":["25170085"],"is_preprint":false},{"year":2004,"finding":"NUFIP (NUFIP1) interacts with BRCA1 (identified by yeast two-hybrid) and with the P-TEFb complex via its Cyclin T1 subunit. NUFIP stimulates activator-independent RNA polymerase II transcription in vitro and in vivo; immunodepletion of endogenous NUFIP markedly decreases pol II transcription. NUFIP associates with preinitiation, open, and elongation complexes, and facilitates ATP-dependent dissociation of hyperphosphorylated pol II from open transcription complexes in vitro. Mutation of the zinc-finger domain abolishes NUFIP-mediated transcriptional activation.","method":"Yeast two-hybrid, immunodepletion + in vitro transcription assay, co-immunoprecipitation, in vitro transcription reconstitution, zinc-finger domain mutagenesis, in vivo reporter assay in 293 cells","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods (immunodepletion, in vitro assay, mutagenesis, Co-IP), single lab","pmids":["15107825"],"is_preprint":false},{"year":2019,"finding":"Under cyclic mechanical stress (CMS) in trabecular meshwork cells, nuclear LC3 co-immunoprecipitates with NUFIP1 in the nucleolus. NUFIP1 translocates from the nucleus to LAMP2-positive (lysosomal) organelles in mechanically stretched cells, but without triggering ribophagy, suggesting a more general role of NUFIP1 as a selective autophagy receptor for a target other than ribosomes under mechanical stress.","method":"Co-immunoprecipitation, biochemical fractionation, immunofluorescence imaging, adenoviral GFP-LC3 expression, leptomycin B treatment","journal":"Autophagy","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP plus direct imaging with functional inference, single lab, two orthogonal methods","pmids":["31476975"],"is_preprint":false},{"year":2025,"finding":"Under amino acid deficiency, phosphorylated NUFIP1 binds replication protein A2 (RPA32) to recruit the ATR-ATRIP complex, triggering the DNA damage response (DDR). Loss of NUFIP1 impairs the DDR and induces necroptosis-related spontaneous enteritis in vivo; reintroduction of NUFIP1 but not its non-phosphorylatable mutant rescues bowel inflammation in conditional knockout mice.","method":"Co-immunoprecipitation (phospho-NUFIP1 with RPA32/ATR-ATRIP), conditional knockout mouse model, non-phospho-mutant rescue experiments, in vitro cell DDR assays","journal":"Nature metabolism","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP with phospho-mutant rescue in vivo and in vitro, single lab, multiple orthogonal approaches","pmids":["39753713"],"is_preprint":false},{"year":2025,"finding":"In sepsis, ribosome collision activates the cGAS-STING signaling axis, which recruits NUFIP1 to STING protein complexes. NUFIP1-mediated ribophagy suppresses ZBP1-mediated PANoptosome formation and PANoptosis in CD4+ T lymphocytes; NUFIP1 knockdown exacerbates PANoptosis and impairs T cell function (cytokine production, proliferation).","method":"Tandem mass tagging (TMT) proteomics, Co-IP (NUFIP1-STING interaction), NUFIP1 knockdown in Jurkat T cells, cecal ligation and puncture sepsis mouse model, clinical CD4+ T cell analysis","journal":"Research (Washington, D.C.)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP identifying NUFIP1-STING interaction, proteomics, in vitro KD with functional readout, in vivo model, single lab","pmids":["40995563"],"is_preprint":false},{"year":2022,"finding":"In cancer-associated fibroblasts (CAFs), NUFIP1-dependent autophagy (ribophagy) mediates secretion of nucleosides that support pancreatic tumor growth and glucose utilization under glutamine deprivation. Inhibiting nucleoside secretion by targeting NUFIP1 in stromal cells reduced tumor weight in an orthotopic mouse model.","method":"NUFIP1 knockdown/inhibition in CAFs, orthotopic PDAC mouse model, metabolite (nucleoside) measurement, MYC-dependence analysis","journal":"Nature cancer","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo orthotopic model with NUFIP1 targeting and nucleoside secretion readout, single lab, multiple methods","pmids":["35982178"],"is_preprint":false}],"current_model":"NUFIP1 is a multifunctional nuclear/cytoplasmic protein that acts as a selective autophagy (ribophagy) receptor by directly binding LC3B to deliver ribosomes to autophagosomes upon mTORC1 inhibition or nutrient starvation; it also scaffolds box C/D snoRNP assembly by interacting with 15.5K/Snu13p and being stabilized by ZNHIT3/Hit1p, stimulates RNA polymerase II transcription in complex with BRCA1 and P-TEFb/Cyclin T1 via its zinc-finger domain, and in its phosphorylated form binds RPA32 to recruit ATR-ATRIP for the DNA damage response, with its ribophagy activity additionally suppressing cGAS-STING-driven PANoptosis in T cells and supporting CAF-mediated nucleoside secretion in the tumor microenvironment."},"narrative":{"mechanistic_narrative":"NUFIP1 is a nucleocytoplasmic shuttling protein that couples ribosome metabolism to selective autophagy and RNA biogenesis [PMID:12941608, PMID:29700228]. It localizes to RNA-containing nuclear matrix structures and to cytoplasmic and ribosome-associated pools, shuttling between compartments through a CRM1-dependent nuclear export signal [PMID:12941608]. In the nucleus it functions as a scaffold/assembly factor for box C/D snoRNPs by directly binding the RNA-binding core protein 15.5K (Snu13p), an interaction defined at residue resolution and predicted to keep snoRNPs in an inactive pre-assembly state; ZNHIT3 (Hit1p homolog) stabilizes NUFIP1 and the resulting heterotrimer engages C/D snoRNAs and the core protein Nop58 [PMID:24234454, PMID:25170085]. NUFIP1 also stimulates RNA polymerase II transcription, acting with BRCA1 and the P-TEFb subunit Cyclin T1 and requiring an intact zinc-finger domain [PMID:15107825]. Its best-characterized role is as a selective autophagy (ribophagy) receptor: upon mTORC1 inhibition or nutrient starvation it relocalizes from the nucleus to autophagosomes and lysosomes and directly binds LC3B to deliver ribosomes for degradation, promoting cell survival [PMID:29700228]. This ribophagy activity is exploited in physiological and disease contexts, supporting nucleoside secretion by cancer-associated fibroblasts to fuel pancreatic tumor growth [PMID:35982178] and suppressing cGAS-STING- and ZBP1-driven PANoptosis in CD4+ T cells during sepsis [PMID:40995563]. In a distinct branch, phosphorylated NUFIP1 binds RPA32 under amino acid deprivation to recruit the ATR-ATRIP complex and trigger the DNA damage response, protecting against necroptotic enteritis in vivo [PMID:39753713].","teleology":[{"year":2003,"claim":"Established that NUFIP1 is not a static nuclear protein but actively shuttles between nucleus and cytoplasm and associates with ribosomes, foreshadowing its later dual nuclear/cytoplasmic roles.","evidence":"Subcellular fractionation, immunofluorescence, synaptosome isolation, and leptomycin B inhibition of CRM1-dependent export","pmids":["12941608"],"confidence":"Medium","gaps":["Did not define the cargo or function of cytoplasmic ribosome association","Single lab; export signal mapped functionally but not structurally"]},{"year":2004,"claim":"Identified a nuclear transcriptional role, placing NUFIP1 in complexes with BRCA1 and P-TEFb/Cyclin T1 and showing it is required to stimulate RNA polymerase II transcription via its zinc finger.","evidence":"Yeast two-hybrid, immunodepletion plus in vitro transcription, Co-IP, zinc-finger mutagenesis, reporter assays in 293 cells","pmids":["15107825"],"confidence":"Medium","gaps":["Mechanism by which NUFIP1 dissociates hyperphosphorylated pol II not structurally resolved","Functional link between BRCA1 and Cyclin T1 binding not established","Single lab"]},{"year":2013,"claim":"Defined NUFIP1 (Rsa1p homolog) as a box C/D snoRNP assembly scaffold, mapping its direct interface with the 15.5K/Snu13p core protein and proposing it blocks premature snoRNP activity.","evidence":"NMR structure determination, biophysical binding assays, site-directed mutagenesis with snoRNP formation readouts in yeast, docking","pmids":["24234454"],"confidence":"High","gaps":["Structural work performed on yeast Rsa1p, not human NUFIP1","How assembly is coupled to release of the inactive complex not shown"]},{"year":2014,"claim":"Extended the snoRNP assembly model by showing ZNHIT3 stabilizes NUFIP1 and that a Snu13p-Rsa1p-Hit1p heterotrimer engages C/D snoRNAs and Nop58.","evidence":"Pulldown/MS, NMR structure of yeast Rsa1p-Hit1p, reconstituted heterotrimer binding, snoRNA stability assays, ZNHIT3 regulation of human NUFIP1 abundance","pmids":["25170085"],"confidence":"High","gaps":["Most structural/functional data in yeast; human heterotrimer not reconstituted","Order of assembly events with Nop58 incompletely defined"]},{"year":2018,"claim":"Defined NUFIP1's signature function as a starvation- and mTORC1-regulated ribophagy receptor that binds LC3B to deliver ribosomes to autophagosomes and supports cell survival.","evidence":"Quantitative lysosome proteomics, NUFIP1-LC3B Co-IP, imaging/fractionation, knockdown with survival readout, mTORC1 inhibition","pmids":["29700228"],"confidence":"High","gaps":["How nuclear NUFIP1 is mobilized to autophagosomes mechanistically unresolved","Selectivity determinants for ribosome cargo not fully defined"]},{"year":2019,"claim":"Showed NUFIP1-LC3 engagement is context-dependent, occurring under mechanical stress in trabecular meshwork cells without triggering ribophagy, implying a broader selective-autophagy receptor capacity.","evidence":"Co-IP, biochemical fractionation, immunofluorescence, GFP-LC3 expression, leptomycin B treatment","pmids":["31476975"],"confidence":"Medium","gaps":["The non-ribosomal autophagy target was not identified","Single cell type and lab"]},{"year":2022,"claim":"Connected NUFIP1-dependent ribophagy to tumor metabolism, showing it drives nucleoside secretion by cancer-associated fibroblasts that fuels pancreatic tumor growth.","evidence":"NUFIP1 knockdown/inhibition in CAFs, orthotopic PDAC model, nucleoside metabolite measurement, MYC-dependence analysis","pmids":["35982178"],"confidence":"Medium","gaps":["Direct link between ribophagy flux and nucleoside output not biochemically traced","Single lab"]},{"year":2025,"claim":"Revealed a phosphorylation-dependent DNA damage response role in which NUFIP1 binds RPA32 to recruit ATR-ATRIP under amino acid deprivation, protecting intestinal tissue from necroptotic inflammation.","evidence":"Phospho-NUFIP1 Co-IP with RPA32/ATR-ATRIP, conditional knockout mice, non-phosphorylatable mutant rescue, in vitro DDR assays","pmids":["39753713"],"confidence":"Medium","gaps":["Kinase responsible for NUFIP1 phosphorylation not identified","Relationship between this DDR role and ribophagy unresolved","Single lab"]},{"year":2025,"claim":"Linked NUFIP1 ribophagy to innate immune cell death control, showing ribosome collision recruits NUFIP1 to STING and that NUFIP1-mediated ribophagy suppresses ZBP1-driven PANoptosis in CD4+ T cells in sepsis.","evidence":"TMT proteomics, NUFIP1-STING Co-IP, knockdown in Jurkat cells, cecal ligation/puncture model, clinical CD4+ T cell analysis","pmids":["40995563"],"confidence":"Medium","gaps":["Mechanism coupling ribosome collision to NUFIP1 recruitment not defined","Direct interaction vs indirect STING association not fully distinguished","Single lab"]},{"year":null,"claim":"How NUFIP1's distinct activities — nuclear snoRNP assembly and transcription, cytoplasmic ribophagy, and phospho-dependent DDR signaling — are coordinated and switched in response to nutrient and stress cues remains unknown.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unified regulatory model linking nuclear and autophagy functions","Human structural data for the LC3B and RPA32 interactions lacking","Switch from snoRNP/transcription roles to ribophagy receptor not mechanistically explained"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0003723","term_label":"RNA binding","supporting_discovery_ids":[2,3]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[0,2,3]},{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[4]}],"localization":[{"term_id":"GO:0005730","term_label":"nucleolus","supporting_discovery_ids":[1,5]},{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[0,1]},{"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:0005840","term_label":"ribosome","supporting_discovery_ids":[1]}],"pathway":[{"term_id":"R-HSA-9612973","term_label":"Autophagy","supporting_discovery_ids":[0,5,8,7]},{"term_id":"R-HSA-8953854","term_label":"Metabolism of RNA","supporting_discovery_ids":[2,3]},{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[4]},{"term_id":"R-HSA-73894","term_label":"DNA Repair","supporting_discovery_ids":[6]}],"complexes":["box C/D snoRNP assembly complex (Snu13p/15.5K-Rsa1p/NUFIP1-Hit1p/ZNHIT3)","P-TEFb"],"partners":["MAP1LC3B","SNU13","ZNHIT3","BRCA1","CCNT1","RPA32","ATR","STING1"],"other_free_text":[]}},"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":292,"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":76,"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":47,"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":"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":34,"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":"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":"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":15,"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":"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":13,"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":12420,"output_tokens":2869,"usd":0.040148,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":10165,"output_tokens":3827,"usd":0.07325,"stage2_stop_reason":"end_turn"},"total_usd":0.113398,"stage1_batch_id":"msgbatch_013a8chtv3AWyTqv4z4sEF4C","stage2_batch_id":"msgbatch_01AHsuW63vinsvuTgzmQ3n62","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2018,\n      \"finding\": \"Upon mTORC1 inhibition or nutrient starvation, NUFIP1 redistributes from the nucleus to autophagosomes and lysosomes, where it directly binds LC3B to deliver ribosomes to autophagosomes, functioning as a selective autophagy receptor (ribophagy receptor). This starvation-induced ribophagy depends on the capacity of NUFIP1 to bind LC3B and promotes cell survival.\",\n      \"method\": \"Quantitative lysosome proteomics, co-immunoprecipitation (NUFIP1-LC3B interaction), subcellular fractionation/imaging, loss-of-function (NUFIP1 knockdown with cell survival readout), mTORC1 inhibition experiments\",\n      \"journal\": \"Science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (proteomics, Co-IP, imaging, functional KD with survival readout), highly cited, single rigorous study with strong mechanistic validation\",\n      \"pmids\": [\"29700228\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"NUFIP1 is a nucleocytoplasmic shuttling protein: it localizes in the nuclear matrix in RNA-containing structures, is also present in the cytoplasm associated with ribosomes, and is detected in functional synaptoneurosomes in neurons where it co-localizes with ribosomes. NUFIP1 contains a functional CRM1-dependent nuclear export signal mediating its shuttling between nucleus and cytoplasm.\",\n      \"method\": \"Subcellular fractionation, immunofluorescence imaging, synaptosome isolation and immunodetection, leptomycin B (CRM1 inhibitor) treatment demonstrating nuclear export signal function\",\n      \"journal\": \"Experimental cell research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct localization experiments with functional consequence (CRM1-dependent export), single lab, multiple orthogonal methods\",\n      \"pmids\": [\"12941608\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"NUFIP1 (the human homolog of yeast Rsa1p) acts as a scaffold/assembly factor for box C/D snoRNPs by directly interacting with the RNA-binding core protein 15.5K (human homolog of yeast Snu13p). NMR structure determination and docking identified the interface: residues R249, R246, K250 of Rsa1p and E72, D73 of Snu13p form electrostatic interactions, with W253 of Rsa1p inserted in a hydrophobic cavity of Snu13p. This interaction is predicted to be exclusive of interactions in active snoRNPs, suggesting Rsa1p/NUFIP1 prevents premature snoRNP activity.\",\n      \"method\": \"NMR structure determination, biophysical interaction assays, site-directed mutagenesis in yeast (cell growth and snoRNP formation readouts), molecular docking\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — NMR structure plus mutagenesis plus functional validation in yeast, multiple orthogonal methods in one rigorous study\",\n      \"pmids\": [\"24234454\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"NUFIP1 (human functional homolog of yeast Rsa1p) interacts with ZNHIT3 (TRIP3, human homolog of yeast Hit1p), which stabilizes NUFIP1 protein levels. The yeast Rsa1p-Hit1p complex structure was determined by NMR, revealing a novel mode of protein-protein association. The purified Snu13p-Rsa1p-Hit1p heterotrimer can interact with C/D snoRNAs and core protein Nop58, placing NUFIP1 within the snoRNP assembly pathway.\",\n      \"method\": \"Proteomic (pulldown/MS), NMR structure determination of yeast Rsa1p-Hit1p complex, functional studies (C/D snoRNA stability, pre-RNA maturation), in vitro binding with purified heterotrimer, demonstration that human ZNHIT3 regulates NUFIP1 abundance\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — NMR structure of the complex, reconstituted heterotrimer binding, functional readouts, with human NUFIP1 regulatory finding included\",\n      \"pmids\": [\"25170085\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"NUFIP (NUFIP1) interacts with BRCA1 (identified by yeast two-hybrid) and with the P-TEFb complex via its Cyclin T1 subunit. NUFIP stimulates activator-independent RNA polymerase II transcription in vitro and in vivo; immunodepletion of endogenous NUFIP markedly decreases pol II transcription. NUFIP associates with preinitiation, open, and elongation complexes, and facilitates ATP-dependent dissociation of hyperphosphorylated pol II from open transcription complexes in vitro. Mutation of the zinc-finger domain abolishes NUFIP-mediated transcriptional activation.\",\n      \"method\": \"Yeast two-hybrid, immunodepletion + in vitro transcription assay, co-immunoprecipitation, in vitro transcription reconstitution, zinc-finger domain mutagenesis, in vivo reporter assay in 293 cells\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods (immunodepletion, in vitro assay, mutagenesis, Co-IP), single lab\",\n      \"pmids\": [\"15107825\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Under cyclic mechanical stress (CMS) in trabecular meshwork cells, nuclear LC3 co-immunoprecipitates with NUFIP1 in the nucleolus. NUFIP1 translocates from the nucleus to LAMP2-positive (lysosomal) organelles in mechanically stretched cells, but without triggering ribophagy, suggesting a more general role of NUFIP1 as a selective autophagy receptor for a target other than ribosomes under mechanical stress.\",\n      \"method\": \"Co-immunoprecipitation, biochemical fractionation, immunofluorescence imaging, adenoviral GFP-LC3 expression, leptomycin B treatment\",\n      \"journal\": \"Autophagy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP plus direct imaging with functional inference, single lab, two orthogonal methods\",\n      \"pmids\": [\"31476975\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Under amino acid deficiency, phosphorylated NUFIP1 binds replication protein A2 (RPA32) to recruit the ATR-ATRIP complex, triggering the DNA damage response (DDR). Loss of NUFIP1 impairs the DDR and induces necroptosis-related spontaneous enteritis in vivo; reintroduction of NUFIP1 but not its non-phosphorylatable mutant rescues bowel inflammation in conditional knockout mice.\",\n      \"method\": \"Co-immunoprecipitation (phospho-NUFIP1 with RPA32/ATR-ATRIP), conditional knockout mouse model, non-phospho-mutant rescue experiments, in vitro cell DDR assays\",\n      \"journal\": \"Nature metabolism\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP with phospho-mutant rescue in vivo and in vitro, single lab, multiple orthogonal approaches\",\n      \"pmids\": [\"39753713\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"In sepsis, ribosome collision activates the cGAS-STING signaling axis, which recruits NUFIP1 to STING protein complexes. NUFIP1-mediated ribophagy suppresses ZBP1-mediated PANoptosome formation and PANoptosis in CD4+ T lymphocytes; NUFIP1 knockdown exacerbates PANoptosis and impairs T cell function (cytokine production, proliferation).\",\n      \"method\": \"Tandem mass tagging (TMT) proteomics, Co-IP (NUFIP1-STING interaction), NUFIP1 knockdown in Jurkat T cells, cecal ligation and puncture sepsis mouse model, clinical CD4+ T cell analysis\",\n      \"journal\": \"Research (Washington, D.C.)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP identifying NUFIP1-STING interaction, proteomics, in vitro KD with functional readout, in vivo model, single lab\",\n      \"pmids\": [\"40995563\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"In cancer-associated fibroblasts (CAFs), NUFIP1-dependent autophagy (ribophagy) mediates secretion of nucleosides that support pancreatic tumor growth and glucose utilization under glutamine deprivation. Inhibiting nucleoside secretion by targeting NUFIP1 in stromal cells reduced tumor weight in an orthotopic mouse model.\",\n      \"method\": \"NUFIP1 knockdown/inhibition in CAFs, orthotopic PDAC mouse model, metabolite (nucleoside) measurement, MYC-dependence analysis\",\n      \"journal\": \"Nature cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo orthotopic model with NUFIP1 targeting and nucleoside secretion readout, single lab, multiple methods\",\n      \"pmids\": [\"35982178\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"NUFIP1 is a multifunctional nuclear/cytoplasmic protein that acts as a selective autophagy (ribophagy) receptor by directly binding LC3B to deliver ribosomes to autophagosomes upon mTORC1 inhibition or nutrient starvation; it also scaffolds box C/D snoRNP assembly by interacting with 15.5K/Snu13p and being stabilized by ZNHIT3/Hit1p, stimulates RNA polymerase II transcription in complex with BRCA1 and P-TEFb/Cyclin T1 via its zinc-finger domain, and in its phosphorylated form binds RPA32 to recruit ATR-ATRIP for the DNA damage response, with its ribophagy activity additionally suppressing cGAS-STING-driven PANoptosis in T cells and supporting CAF-mediated nucleoside secretion in the tumor microenvironment.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"NUFIP1 is a nucleocytoplasmic shuttling protein that couples ribosome metabolism to selective autophagy and RNA biogenesis [#1, #0]. It localizes to RNA-containing nuclear matrix structures and to cytoplasmic and ribosome-associated pools, shuttling between compartments through a CRM1-dependent nuclear export signal [#1]. In the nucleus it functions as a scaffold/assembly factor for box C/D snoRNPs by directly binding the RNA-binding core protein 15.5K (Snu13p), an interaction defined at residue resolution and predicted to keep snoRNPs in an inactive pre-assembly state; ZNHIT3 (Hit1p homolog) stabilizes NUFIP1 and the resulting heterotrimer engages C/D snoRNAs and the core protein Nop58 [#2, #3]. NUFIP1 also stimulates RNA polymerase II transcription, acting with BRCA1 and the P-TEFb subunit Cyclin T1 and requiring an intact zinc-finger domain [#4]. Its best-characterized role is as a selective autophagy (ribophagy) receptor: upon mTORC1 inhibition or nutrient starvation it relocalizes from the nucleus to autophagosomes and lysosomes and directly binds LC3B to deliver ribosomes for degradation, promoting cell survival [#0]. This ribophagy activity is exploited in physiological and disease contexts, supporting nucleoside secretion by cancer-associated fibroblasts to fuel pancreatic tumor growth [#8] and suppressing cGAS-STING- and ZBP1-driven PANoptosis in CD4+ T cells during sepsis [#7]. In a distinct branch, phosphorylated NUFIP1 binds RPA32 under amino acid deprivation to recruit the ATR-ATRIP complex and trigger the DNA damage response, protecting against necroptotic enteritis in vivo [#6].\"\n,\n  \"teleology\": [\n    {\n      \"year\": 2003,\n      \"claim\": \"Established that NUFIP1 is not a static nuclear protein but actively shuttles between nucleus and cytoplasm and associates with ribosomes, foreshadowing its later dual nuclear/cytoplasmic roles.\",\n      \"evidence\": \"Subcellular fractionation, immunofluorescence, synaptosome isolation, and leptomycin B inhibition of CRM1-dependent export\",\n      \"pmids\": [\"12941608\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Did not define the cargo or function of cytoplasmic ribosome association\", \"Single lab; export signal mapped functionally but not structurally\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Identified a nuclear transcriptional role, placing NUFIP1 in complexes with BRCA1 and P-TEFb/Cyclin T1 and showing it is required to stimulate RNA polymerase II transcription via its zinc finger.\",\n      \"evidence\": \"Yeast two-hybrid, immunodepletion plus in vitro transcription, Co-IP, zinc-finger mutagenesis, reporter assays in 293 cells\",\n      \"pmids\": [\"15107825\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism by which NUFIP1 dissociates hyperphosphorylated pol II not structurally resolved\", \"Functional link between BRCA1 and Cyclin T1 binding not established\", \"Single lab\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Defined NUFIP1 (Rsa1p homolog) as a box C/D snoRNP assembly scaffold, mapping its direct interface with the 15.5K/Snu13p core protein and proposing it blocks premature snoRNP activity.\",\n      \"evidence\": \"NMR structure determination, biophysical binding assays, site-directed mutagenesis with snoRNP formation readouts in yeast, docking\",\n      \"pmids\": [\"24234454\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural work performed on yeast Rsa1p, not human NUFIP1\", \"How assembly is coupled to release of the inactive complex not shown\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Extended the snoRNP assembly model by showing ZNHIT3 stabilizes NUFIP1 and that a Snu13p-Rsa1p-Hit1p heterotrimer engages C/D snoRNAs and Nop58.\",\n      \"evidence\": \"Pulldown/MS, NMR structure of yeast Rsa1p-Hit1p, reconstituted heterotrimer binding, snoRNA stability assays, ZNHIT3 regulation of human NUFIP1 abundance\",\n      \"pmids\": [\"25170085\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Most structural/functional data in yeast; human heterotrimer not reconstituted\", \"Order of assembly events with Nop58 incompletely defined\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Defined NUFIP1's signature function as a starvation- and mTORC1-regulated ribophagy receptor that binds LC3B to deliver ribosomes to autophagosomes and supports cell survival.\",\n      \"evidence\": \"Quantitative lysosome proteomics, NUFIP1-LC3B Co-IP, imaging/fractionation, knockdown with survival readout, mTORC1 inhibition\",\n      \"pmids\": [\"29700228\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How nuclear NUFIP1 is mobilized to autophagosomes mechanistically unresolved\", \"Selectivity determinants for ribosome cargo not fully defined\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Showed NUFIP1-LC3 engagement is context-dependent, occurring under mechanical stress in trabecular meshwork cells without triggering ribophagy, implying a broader selective-autophagy receptor capacity.\",\n      \"evidence\": \"Co-IP, biochemical fractionation, immunofluorescence, GFP-LC3 expression, leptomycin B treatment\",\n      \"pmids\": [\"31476975\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"The non-ribosomal autophagy target was not identified\", \"Single cell type and lab\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Connected NUFIP1-dependent ribophagy to tumor metabolism, showing it drives nucleoside secretion by cancer-associated fibroblasts that fuels pancreatic tumor growth.\",\n      \"evidence\": \"NUFIP1 knockdown/inhibition in CAFs, orthotopic PDAC model, nucleoside metabolite measurement, MYC-dependence analysis\",\n      \"pmids\": [\"35982178\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct link between ribophagy flux and nucleoside output not biochemically traced\", \"Single lab\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Revealed a phosphorylation-dependent DNA damage response role in which NUFIP1 binds RPA32 to recruit ATR-ATRIP under amino acid deprivation, protecting intestinal tissue from necroptotic inflammation.\",\n      \"evidence\": \"Phospho-NUFIP1 Co-IP with RPA32/ATR-ATRIP, conditional knockout mice, non-phosphorylatable mutant rescue, in vitro DDR assays\",\n      \"pmids\": [\"39753713\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Kinase responsible for NUFIP1 phosphorylation not identified\", \"Relationship between this DDR role and ribophagy unresolved\", \"Single lab\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Linked NUFIP1 ribophagy to innate immune cell death control, showing ribosome collision recruits NUFIP1 to STING and that NUFIP1-mediated ribophagy suppresses ZBP1-driven PANoptosis in CD4+ T cells in sepsis.\",\n      \"evidence\": \"TMT proteomics, NUFIP1-STING Co-IP, knockdown in Jurkat cells, cecal ligation/puncture model, clinical CD4+ T cell analysis\",\n      \"pmids\": [\"40995563\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism coupling ribosome collision to NUFIP1 recruitment not defined\", \"Direct interaction vs indirect STING association not fully distinguished\", \"Single lab\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How NUFIP1's distinct activities — nuclear snoRNP assembly and transcription, cytoplasmic ribophagy, and phospho-dependent DDR signaling — are coordinated and switched in response to nutrient and stress cues remains unknown.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unified regulatory model linking nuclear and autophagy functions\", \"Human structural data for the LC3B and RPA32 interactions lacking\", \"Switch from snoRNP/transcription roles to ribophagy receptor not mechanistically explained\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0003723\", \"supporting_discovery_ids\": [2, 3]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [0, 2, 3]},\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [4]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005730\", \"supporting_discovery_ids\": [1, 5]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [0, 1]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [1]},\n      {\"term_id\": \"GO:0005764\", \"supporting_discovery_ids\": [0, 5]},\n      {\"term_id\": \"GO:0005840\", \"supporting_discovery_ids\": [1]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-9612973\", \"supporting_discovery_ids\": [0, 5, 8, 7]},\n      {\"term_id\": \"R-HSA-8953854\", \"supporting_discovery_ids\": [2, 3]},\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [4]},\n      {\"term_id\": \"R-HSA-73894\", \"supporting_discovery_ids\": [6]}\n    ],\n    \"complexes\": [\"box C/D snoRNP assembly complex (Snu13p/15.5K-Rsa1p/NUFIP1-Hit1p/ZNHIT3)\", \"P-TEFb\"],\n    \"partners\": [\"MAP1LC3B\", \"SNU13\", \"ZNHIT3\", \"BRCA1\", \"CCNT1\", \"RPA32\", \"ATR\", \"STING1\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"faith_supported":7,"faith_total":7,"faith_pct":100.0}}