{"gene":"UBAP1","run_date":"2026-04-28T21:43:00","timeline":{"discoveries":[{"year":2011,"finding":"UBAP1 is a novel subunit of an endosome-specific ESCRT-I complex containing TSG101, VPS28, and VPS37A (but not VPS37C). UBAP1 contains a region conserved in MVB12, binds the endosomal Bro1 protein HDPTP (but not Alix), is required for sorting EGFR to the MVB and for endosomal ubiquitin homeostasis, but is not required for cytokinesis.","method":"Co-immunoprecipitation, siRNA knockdown, subcellular fractionation, fluorescence microscopy, functional sorting assays","journal":"Current biology : CB","confidence":"High","confidence_rationale":"Tier 2 — reciprocal Co-IP, clean KD with defined cellular phenotypes, replicated across multiple assays; highly cited foundational paper","pmids":["21757351"],"is_preprint":false},{"year":2012,"finding":"UBAP1 co-assembles in a stable 1:1:1:1 complex with TSG101/Vps23, VPS28, and VPS37. The C-terminal region of UBAP1 forms a SOUBA (solenoid of overlapping UBAs) domain in which each of three rigidly arranged overlapping UBA motifs independently interacts with ubiquitin, as shown by X-ray crystallography and NMR. UBAP1-containing ESCRT-I is required for degradation of antiviral cell-surface proteins tetherin (BST-2/CD317) by HIV-1 Vpu and KSHV K5.","method":"X-ray crystallography, NMR analysis, biochemical reconstitution, functional assays (antiviral protein degradation)","journal":"Structure (London, England : 1993)","confidence":"High","confidence_rationale":"Tier 1 — crystal structure, NMR with functional validation, reconstituted complex; strong/moderate evidence","pmids":["22405001"],"is_preprint":false},{"year":2013,"finding":"The incorporation of UBAP1 into ESCRT-I is highly selective for VPS37A over other VPS37 paralogs. The region mediating selective assembly maps to the core ESCRT-I-binding domain of VPS37A, and UBAP1 requires both its minimal ESCRT-I-binding region and a neighbouring predicted helix. Functional specialization is confirmed: siRNA depletion of UBAP1, but not MVB12A or MVB12B, disrupts ubiquitin-dependent MVB sorting.","method":"Domain mapping by mutagenesis, siRNA knockdown, co-immunoprecipitation, ubiquitin-dependent cargo sorting assays","journal":"Journal of cell science","confidence":"High","confidence_rationale":"Tier 2 — reciprocal Co-IP, mutagenesis mapping, clean KD with defined sorting phenotype; moderate evidence","pmids":["24284069"],"is_preprint":false},{"year":2017,"finding":"The Pseudomonas aeruginosa TIR effector PumA interacts directly with UBAP1 (as well as TLR adaptors TIRAP and MyD88). UBAP1 itself associates with MyD88 and enhances its plasma membrane localization. Combined targeting of UBAP1 and TLR adaptors by PumA impedes cytokine and TLR receptor signalling.","method":"Co-immunoprecipitation, pulldown, subcellular localization assays, NF-κB reporter assays","journal":"The EMBO journal","confidence":"Medium","confidence_rationale":"Tier 2/3 — Co-IP and localization data in a single study; moderate mechanistic follow-up","pmids":["28483816"],"is_preprint":false},{"year":2019,"finding":"Truncating mutations in UBAP1 (within a circumscript region, exon 4 hotspot) cause autosomal-dominant hereditary spastic paraplegia (SPG80). mRNA from affected individuals escapes nonsense-mediated decay, producing truncated proteins; full-length protein levels are also reduced. Patient-derived truncated UBAP1 causes aberrant endosome clustering, pronounced endosome enlargement, and cytoplasmic accumulation of ubiquitinated proteins in HeLa cells and cortical neurons. Disruption of UBAP1 leads to dysregulation of early endosome processing and ubiquitinated protein sorting, and promotes neurodegeneration potentially via apoptosis.","method":"Whole-exome sequencing, mRNA decay analysis, overexpression of truncated UBAP1 in HeLa cells and cortical neurons, immunocytochemistry, zebrafish knockdown","journal":"American journal of human genetics / Brain : a journal of neurology","confidence":"High","confidence_rationale":"Tier 2 — multiple labs, orthogonal biochemical and cellular methods, replicated across multiple studies","pmids":["30929741","31203368","31515522"],"is_preprint":false},{"year":2019,"finding":"A C-terminal deletion UBAP1 mutant (disease model) loses the ability to bind ubiquitin in vitro and cannot be recruited to endosome membranes in mouse hippocampal neurons, whereas wild-type UBAP1 directly interacts with ubiquitin on enlarged endosomes. This indicates the SOUBA/C-terminal domain is required for endosomal targeting.","method":"In vitro ubiquitin-binding assay, overexpression in primary neurons, fluorescence microscopy","journal":"Journal of human genetics","confidence":"Medium","confidence_rationale":"Tier 2 — in vitro binding assay plus localization in primary neurons; single lab","pmids":["31515522"],"is_preprint":false},{"year":2022,"finding":"Ubap1+/E176Efx23 knock-in mice (heterozygous truncating mutation that deletes the SOUBA domain while leaving the UMA domain intact) develop progressive hind limb dysfunction, show spinal cord neuron loss and accumulation of ubiquitinated proteins, and display altered distributions of Rab5 and Rab7 in the spinal cord, indicating that UBAP1 truncation disturbs endosome-mediated vesicular trafficking in vivo.","method":"Knock-in mouse model, behavioral assays, immunohistochemistry, Rab5/Rab7 distribution analysis","journal":"Journal of human genetics","confidence":"Medium","confidence_rationale":"Tier 2 — in vivo knock-in model with defined molecular readouts; single lab","pmids":["35962060"],"is_preprint":false},{"year":2024,"finding":"Conditional disruption of UBAP1 in radial glial cells causes severe brain dysplasia and prenatal ventriculomegaly. UBAP1 depletion disrupts adherens junctions (AJs) and polarity of radial glial cells (RGCs), leading to failure of apically directed interkinetic nuclear migration, reduced proliferation, and precocious differentiation of neural progenitor cells. Mechanistically, UBAP1 regulates surface localization of cell adhesion molecules, and β-catenin overexpression significantly rescues Ubap1 knockdown phenotypes in vivo.","method":"Conditional knockout, in utero knockdown, immunofluorescence, live imaging, β-catenin rescue experiment","journal":"Cell reports","confidence":"Medium","confidence_rationale":"Tier 2 — conditional KO with defined cellular phenotypes and genetic rescue; single lab","pmids":["38402586"],"is_preprint":false}],"current_model":"UBAP1 is an endosome-specific subunit of the ESCRT-I complex (together with TSG101, VPS28, and VPS37A) whose C-terminal SOUBA domain structurally binds ubiquitin through three overlapping UBA motifs, enabling ubiquitin-dependent MVB cargo sorting (e.g., EGFR, tetherin); selective assembly with VPS37A (not VPS37C) restricts its function to endosomal sorting rather than cytokinesis, and truncating mutations that abolish ubiquitin binding and endosomal targeting cause autosomal-dominant hereditary spastic paraplegia (SPG80) by disrupting endosomal trafficking, ubiquitinated protein homeostasis, and, in radial glia, adherens junction regulation during cortical neurogenesis."},"narrative":{"teleology":[{"year":2011,"claim":"Identifying UBAP1 as an ESCRT-I subunit resolved how the endosomal ESCRT-I complex differs compositionally from the cytokinetic pool, establishing that UBAP1 confers endosome-specific cargo sorting function.","evidence":"Reciprocal co-immunoprecipitation, siRNA knockdown with EGFR sorting and ubiquitin homeostasis readouts in human cells","pmids":["21757351"],"confidence":"High","gaps":["Structural basis of UBAP1–ubiquitin interaction not yet defined","Why UBAP1 selects VPS37A over VPS37C not mapped","In vivo significance in neuronal tissues unknown"]},{"year":2012,"claim":"Solving the SOUBA domain crystal structure revealed a unique triple-UBA solenoid architecture for ubiquitin recognition, explaining how UBAP1 captures ubiquitinated cargo and showing it is functionally required for viral exploitation of ESCRT-I (tetherin degradation by HIV-1 Vpu and KSHV K5).","evidence":"X-ray crystallography, NMR titration, reconstituted ESCRT-I complex, antiviral protein degradation assays","pmids":["22405001"],"confidence":"High","gaps":["Quantitative affinity and selectivity for different ubiquitin chain types not determined","Whether SOUBA domain alone is sufficient for endosomal targeting unclear"]},{"year":2013,"claim":"Mapping the selective UBAP1–VPS37A assembly interface clarified why UBAP1 is excluded from MVB12-containing and cytokinetic ESCRT-I complexes, establishing paralog-specific functional specialization within ESCRT-I.","evidence":"Domain deletion/mutagenesis, co-immunoprecipitation, siRNA-based cargo sorting assays","pmids":["24284069"],"confidence":"High","gaps":["Atomic-resolution interface between UBAP1 and VPS37A not solved","Whether other post-translational modifications regulate assembly unknown"]},{"year":2017,"claim":"Discovery that the bacterial effector PumA targets UBAP1 alongside TLR adaptors revealed a previously unrecognized connection between UBAP1/ESCRT-I and innate immune receptor trafficking.","evidence":"Co-immunoprecipitation, NF-κB reporter assays, subcellular localization of MyD88","pmids":["28483816"],"confidence":"Medium","gaps":["Direct binding interface between PumA and UBAP1 not mapped","Physiological relevance of UBAP1–MyD88 interaction in vivo not tested","Not independently confirmed by a second group"]},{"year":2019,"claim":"Identification of truncating UBAP1 mutations as the cause of SPG80 established that loss of UBAP1's ubiquitin-binding and endosomal sorting function leads to human neurodegeneration, linking ESCRT-I dysfunction to hereditary spastic paraplegia.","evidence":"Whole-exome sequencing in multiple families, mRNA decay analysis, overexpression of truncated UBAP1 in HeLa/cortical neurons, in vitro ubiquitin-binding assays, zebrafish knockdown","pmids":["30929741","31203368","31515522"],"confidence":"High","gaps":["Whether truncated protein exerts dominant-negative or haploinsufficiency effect not resolved","Cell-type-specific vulnerability of upper motor neurons not explained","Downstream apoptotic pathways not delineated"]},{"year":2022,"claim":"A heterozygous knock-in mouse model recapitulated progressive motor dysfunction and spinal cord pathology of SPG80, demonstrating in vivo that SOUBA domain loss disrupts Rab5/Rab7-marked endosomal trafficking and causes ubiquitinated protein accumulation in neurons.","evidence":"Ubap1+/E176Efx23 knock-in mice, behavioral assays, immunohistochemistry, Rab distribution analysis","pmids":["35962060"],"confidence":"Medium","gaps":["Single lab; independent replication pending","Whether corticospinal tract specifically degenerates not shown","Temporal sequence of endosomal dysfunction versus neurodegeneration not dissected"]},{"year":2024,"claim":"Conditional loss of UBAP1 in radial glia revealed a critical role in maintaining adherens junctions and apical-basal polarity during cortical neurogenesis, with β-catenin rescue demonstrating that UBAP1 regulates surface adhesion molecule homeostasis upstream of Wnt/β-catenin signaling.","evidence":"Conditional knockout and in utero knockdown in mouse brain, live imaging, β-catenin overexpression rescue","pmids":["38402586"],"confidence":"Medium","gaps":["Single lab; independent replication pending","Which specific adhesion molecules are UBAP1 cargo not identified","Whether this developmental role contributes to SPG80 disease pathogenesis not established"]},{"year":null,"claim":"It remains unknown which specific ubiquitinated cargo proteins are sorted by UBAP1-containing ESCRT-I in motor neurons, how truncated UBAP1 protein mechanistically exerts its dominant effect, and whether therapeutic restoration of endosomal sorting can prevent SPG80 neurodegeneration.","evidence":"","pmids":[],"confidence":"Low","gaps":["Neuron-specific UBAP1 cargo repertoire uncharacterized","Dominant-negative versus haploinsufficiency mechanism unresolved","No therapeutic rescue demonstrated in mammalian models"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[0,2]},{"term_id":"GO:0008289","term_label":"lipid binding","supporting_discovery_ids":[1,5]}],"localization":[{"term_id":"GO:0005768","term_label":"endosome","supporting_discovery_ids":[0,4,5,6]},{"term_id":"GO:0031410","term_label":"cytoplasmic vesicle","supporting_discovery_ids":[0,6]}],"pathway":[{"term_id":"R-HSA-5653656","term_label":"Vesicle-mediated transport","supporting_discovery_ids":[0,1,2,4,6]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[7]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[4,6]}],"complexes":["ESCRT-I"],"partners":["TSG101","VPS28","VPS37A","HDPTP","MYOD88"],"other_free_text":[]},"mechanistic_narrative":"UBAP1 is an endosome-specific subunit of the ESCRT-I complex that mediates ubiquitin-dependent sorting of membrane cargo into multivesicular bodies. It assembles in a 1:1:1:1 stoichiometry with TSG101, VPS28, and selectively VPS37A (not VPS37C), restricting its function to endosomal sorting rather than cytokinesis; its C-terminal SOUBA domain, comprising three overlapping UBA motifs resolved by crystallography and NMR, independently binds ubiquitin and is required for endosomal membrane recruitment [PMID:21757351, PMID:22405001, PMID:24284069]. UBAP1 is essential for degradative sorting of receptors such as EGFR and tetherin, for endosomal ubiquitin homeostasis, and in radial glia for maintaining adherens junctions and apical polarity during cortical neurogenesis [PMID:21757351, PMID:22405001, PMID:38402586]. Heterozygous truncating mutations in UBAP1 that delete the SOUBA domain cause autosomal-dominant hereditary spastic paraplegia (SPG80), characterized by aberrant endosome morphology, cytoplasmic accumulation of ubiquitinated proteins, and progressive motor neuron degeneration [PMID:30929741, PMID:35962060]."},"prefetch_data":{"uniprot":{"accession":"Q9NZ09","full_name":"Ubiquitin-associated protein 1","aliases":["Nasopharyngeal carcinoma-associated gene 20 protein"],"length_aa":502,"mass_kda":55.1,"function":"Component of the ESCRT-I complex, a regulator of vesicular trafficking process (PubMed:21757351, PubMed:22405001, PubMed:31203368). Binds to ubiquitinated cargo proteins and is required for the sorting of endocytic ubiquitinated cargos into multivesicular bodies (MVBs) (PubMed:21757351, PubMed:22405001). Plays a role in the proteasomal degradation of ubiquitinated cell-surface proteins, such as EGFR and BST2 (PubMed:22405001, PubMed:24284069, PubMed:31203368)","subcellular_location":"Cytoplasm, cytosol; Endosome","url":"https://www.uniprot.org/uniprotkb/Q9NZ09/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":true,"resolved_as":"","url":"https://depmap.org/portal/gene/UBAP1","classification":"Common Essential","n_dependent_lines":1091,"n_total_lines":1208,"dependency_fraction":0.9031456953642384},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"TSG101","stoichiometry":10.0},{"gene":"VPS28","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/UBAP1","total_profiled":1310},"omim":[{"mim_id":"621543","title":"UBIQUITIN-ASSOCIATED PROTEIN 1-LIKE PROTEIN; UBAP1L","url":"https://www.omim.org/entry/621543"},{"mim_id":"621453","title":"MULTIVESICULAR BODY SUBUNIT 12A; MVB12A","url":"https://www.omim.org/entry/621453"},{"mim_id":"620252","title":"TRANSMEMBRANE PROTEIN 245; TMEM245","url":"https://www.omim.org/entry/620252"},{"mim_id":"618418","title":"SPASTIC PARAPLEGIA 80, AUTOSOMAL DOMINANT; SPG80","url":"https://www.omim.org/entry/618418"},{"mim_id":"609787","title":"UBIQUITIN-ASSOCIATED PROTEIN 1; UBAP1","url":"https://www.omim.org/entry/609787"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Cytosol","reliability":"Supported"},{"location":"Vesicles","reliability":"Additional"},{"location":"Plasma membrane","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/UBAP1"},"hgnc":{"alias_symbol":[],"prev_symbol":["UBAP"]},"alphafold":{"accession":"Q9NZ09","domains":[{"cath_id":"1.20.120.1920","chopping":"388-438","consensus_level":"medium","plddt":89.9625,"start":388,"end":438},{"cath_id":"1.20.120.1920","chopping":"440-502","consensus_level":"medium","plddt":88.6673,"start":440,"end":502}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9NZ09","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9NZ09-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9NZ09-F1-predicted_aligned_error_v6.png","plddt_mean":62.5},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=UBAP1","jax_strain_url":"https://www.jax.org/strain/search?query=UBAP1"},"sequence":{"accession":"Q9NZ09","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9NZ09.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9NZ09/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9NZ09"}},"corpus_meta":[{"pmid":"21757351","id":"PMC_21757351","title":"UBAP1 is a component of an endosome-specific ESCRT-I complex that is essential for MVB sorting.","date":"2011","source":"Current biology : CB","url":"https://pubmed.ncbi.nlm.nih.gov/21757351","citation_count":110,"is_preprint":false},{"pmid":"22405001","id":"PMC_22405001","title":"The UBAP1 subunit of ESCRT-I interacts with ubiquitin via a SOUBA domain.","date":"2012","source":"Structure (London, England : 1993)","url":"https://pubmed.ncbi.nlm.nih.gov/22405001","citation_count":95,"is_preprint":false},{"pmid":"30929741","id":"PMC_30929741","title":"Truncating Mutations in UBAP1 Cause Hereditary Spastic Paraplegia.","date":"2019","source":"American journal of human genetics","url":"https://pubmed.ncbi.nlm.nih.gov/30929741","citation_count":50,"is_preprint":false},{"pmid":"31203368","id":"PMC_31203368","title":"Stop-gain mutations in UBAP1 cause pure autosomal-dominant spastic paraplegia.","date":"2019","source":"Brain : a journal of neurology","url":"https://pubmed.ncbi.nlm.nih.gov/31203368","citation_count":34,"is_preprint":false},{"pmid":"28483816","id":"PMC_28483816","title":"A Pseudomonas aeruginosa TIR effector mediates immune evasion by targeting UBAP1 and TLR adaptors.","date":"2017","source":"The EMBO journal","url":"https://pubmed.ncbi.nlm.nih.gov/28483816","citation_count":33,"is_preprint":false},{"pmid":"24284069","id":"PMC_24284069","title":"The molecular basis for selective assembly of the UBAP1-containing endosome-specific ESCRT-I complex.","date":"2013","source":"Journal of cell science","url":"https://pubmed.ncbi.nlm.nih.gov/24284069","citation_count":29,"is_preprint":false},{"pmid":"11599797","id":"PMC_11599797","title":"Isolation and characterization of a novel cDNA, UBAP1, derived from the tumor suppressor locus in human chromosome 9p21-22.","date":"2001","source":"Journal of cancer research and clinical oncology","url":"https://pubmed.ncbi.nlm.nih.gov/11599797","citation_count":24,"is_preprint":false},{"pmid":"31515522","id":"PMC_31515522","title":"UBAP1 mutations cause juvenile-onset hereditary spastic paraplegias (SPG80) and impair UBAP1 targeting to endosomes.","date":"2019","source":"Journal of human genetics","url":"https://pubmed.ncbi.nlm.nih.gov/31515522","citation_count":20,"is_preprint":false},{"pmid":"31696996","id":"PMC_31696996","title":"Truncating variants in UBAP1 associated with childhood-onset nonsyndromic hereditary spastic paraplegia.","date":"2019","source":"Human mutation","url":"https://pubmed.ncbi.nlm.nih.gov/31696996","citation_count":18,"is_preprint":false},{"pmid":"32934340","id":"PMC_32934340","title":"Identification of UBAP1 mutations in juvenile hereditary spastic paraplegia in the 100,000 Genomes Project.","date":"2020","source":"European journal of human genetics : EJHG","url":"https://pubmed.ncbi.nlm.nih.gov/32934340","citation_count":12,"is_preprint":false},{"pmid":"16226037","id":"PMC_16226037","title":"Purification of novel UBAP1 protein and its decreased expression on nasopharyngeal carcinoma tissue microarray.","date":"2005","source":"Protein expression and purification","url":"https://pubmed.ncbi.nlm.nih.gov/16226037","citation_count":11,"is_preprint":false},{"pmid":"32222895","id":"PMC_32222895","title":"Autosomal dominant hereditary spastic paraplegia caused by mutation of UBAP1.","date":"2020","source":"Neurogenetics","url":"https://pubmed.ncbi.nlm.nih.gov/32222895","citation_count":8,"is_preprint":false},{"pmid":"35928447","id":"PMC_35928447","title":"A novel mutation in the UBAP1 gene causing hereditary spastic paraplegia: A case report and overview of the genotype-phenotype correlation.","date":"2022","source":"Frontiers in 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differential expression patterns of a novel human gene (UBAP1) by an expressed sequence tag strategy].","date":"2002","source":"Ai zheng = Aizheng = Chinese journal of cancer","url":"https://pubmed.ncbi.nlm.nih.gov/12451983","citation_count":3,"is_preprint":false},{"pmid":"16708796","id":"PMC_16708796","title":"[Expression and location of UBAP1 protein associated with nasopharyngeal carcinoma].","date":"2005","source":"Zhong nan da xue xue bao. Yi xue ban = Journal of Central South University. Medical sciences","url":"https://pubmed.ncbi.nlm.nih.gov/16708796","citation_count":3,"is_preprint":false},{"pmid":"12050802","id":"PMC_12050802","title":"Cloning and Expression Analysis of a Novel Gene, UBAP1, Possibly Involved in Ubiquitin Pathway.","date":"2001","source":"Sheng wu hua xue yu sheng wu wu li xue bao Acta biochimica et biophysica Sinica","url":"https://pubmed.ncbi.nlm.nih.gov/12050802","citation_count":3,"is_preprint":false},{"pmid":"22404994","id":"PMC_22404994","title":"UBAP1: a new ESCRT member joins the cl_Ub.","date":"2012","source":"Structure (London, England : 1993)","url":"https://pubmed.ncbi.nlm.nih.gov/22404994","citation_count":2,"is_preprint":false},{"pmid":"35321509","id":"PMC_35321509","title":"Novel Frameshift Heterozygous Mutation in UBAP1 Gene Causing Spastic Paraplegia-80: Case Report With Literature Review.","date":"2022","source":"Frontiers in neurology","url":"https://pubmed.ncbi.nlm.nih.gov/35321509","citation_count":1,"is_preprint":false},{"pmid":"41097044","id":"PMC_41097044","title":"4-Phenylbutyric Acid Improves Gait Ability of UBAP1-Related Spastic Paraplegia Mouse Model: Therapeutic Potential for SPG80.","date":"2025","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/41097044","citation_count":0,"is_preprint":false},{"pmid":"39801705","id":"PMC_39801705","title":"Ubiquitin-Associated Protein 1 (UBAP1) Gene Mutation in a 36-Year-Old Filipino Male With Spastic Paraplegia: A Case Report.","date":"2025","source":"Cureus","url":"https://pubmed.ncbi.nlm.nih.gov/39801705","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":11619,"output_tokens":2295,"usd":0.034641},"stage2":{"model":"claude-opus-4-6","input_tokens":5581,"output_tokens":2292,"usd":0.127807},"total_usd":0.162448,"stage1_batch_id":"msgbatch_01RPbVc9PDH9zQmYK5Hs6srm","stage2_batch_id":"msgbatch_01JVbVLzeKN2yVrsGp3zC8aM","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2011,\n      \"finding\": \"UBAP1 is a novel subunit of an endosome-specific ESCRT-I complex containing TSG101, VPS28, and VPS37A (but not VPS37C). UBAP1 contains a region conserved in MVB12, binds the endosomal Bro1 protein HDPTP (but not Alix), is required for sorting EGFR to the MVB and for endosomal ubiquitin homeostasis, but is not required for cytokinesis.\",\n      \"method\": \"Co-immunoprecipitation, siRNA knockdown, subcellular fractionation, fluorescence microscopy, functional sorting assays\",\n      \"journal\": \"Current biology : CB\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal Co-IP, clean KD with defined cellular phenotypes, replicated across multiple assays; highly cited foundational paper\",\n      \"pmids\": [\"21757351\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"UBAP1 co-assembles in a stable 1:1:1:1 complex with TSG101/Vps23, VPS28, and VPS37. The C-terminal region of UBAP1 forms a SOUBA (solenoid of overlapping UBAs) domain in which each of three rigidly arranged overlapping UBA motifs independently interacts with ubiquitin, as shown by X-ray crystallography and NMR. UBAP1-containing ESCRT-I is required for degradation of antiviral cell-surface proteins tetherin (BST-2/CD317) by HIV-1 Vpu and KSHV K5.\",\n      \"method\": \"X-ray crystallography, NMR analysis, biochemical reconstitution, functional assays (antiviral protein degradation)\",\n      \"journal\": \"Structure (London, England : 1993)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — crystal structure, NMR with functional validation, reconstituted complex; strong/moderate evidence\",\n      \"pmids\": [\"22405001\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"The incorporation of UBAP1 into ESCRT-I is highly selective for VPS37A over other VPS37 paralogs. The region mediating selective assembly maps to the core ESCRT-I-binding domain of VPS37A, and UBAP1 requires both its minimal ESCRT-I-binding region and a neighbouring predicted helix. Functional specialization is confirmed: siRNA depletion of UBAP1, but not MVB12A or MVB12B, disrupts ubiquitin-dependent MVB sorting.\",\n      \"method\": \"Domain mapping by mutagenesis, siRNA knockdown, co-immunoprecipitation, ubiquitin-dependent cargo sorting assays\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal Co-IP, mutagenesis mapping, clean KD with defined sorting phenotype; moderate evidence\",\n      \"pmids\": [\"24284069\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"The Pseudomonas aeruginosa TIR effector PumA interacts directly with UBAP1 (as well as TLR adaptors TIRAP and MyD88). UBAP1 itself associates with MyD88 and enhances its plasma membrane localization. Combined targeting of UBAP1 and TLR adaptors by PumA impedes cytokine and TLR receptor signalling.\",\n      \"method\": \"Co-immunoprecipitation, pulldown, subcellular localization assays, NF-κB reporter assays\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2/3 — Co-IP and localization data in a single study; moderate mechanistic follow-up\",\n      \"pmids\": [\"28483816\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Truncating mutations in UBAP1 (within a circumscript region, exon 4 hotspot) cause autosomal-dominant hereditary spastic paraplegia (SPG80). mRNA from affected individuals escapes nonsense-mediated decay, producing truncated proteins; full-length protein levels are also reduced. Patient-derived truncated UBAP1 causes aberrant endosome clustering, pronounced endosome enlargement, and cytoplasmic accumulation of ubiquitinated proteins in HeLa cells and cortical neurons. Disruption of UBAP1 leads to dysregulation of early endosome processing and ubiquitinated protein sorting, and promotes neurodegeneration potentially via apoptosis.\",\n      \"method\": \"Whole-exome sequencing, mRNA decay analysis, overexpression of truncated UBAP1 in HeLa cells and cortical neurons, immunocytochemistry, zebrafish knockdown\",\n      \"journal\": \"American journal of human genetics / Brain : a journal of neurology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple labs, orthogonal biochemical and cellular methods, replicated across multiple studies\",\n      \"pmids\": [\"30929741\", \"31203368\", \"31515522\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"A C-terminal deletion UBAP1 mutant (disease model) loses the ability to bind ubiquitin in vitro and cannot be recruited to endosome membranes in mouse hippocampal neurons, whereas wild-type UBAP1 directly interacts with ubiquitin on enlarged endosomes. This indicates the SOUBA/C-terminal domain is required for endosomal targeting.\",\n      \"method\": \"In vitro ubiquitin-binding assay, overexpression in primary neurons, fluorescence microscopy\",\n      \"journal\": \"Journal of human genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — in vitro binding assay plus localization in primary neurons; single lab\",\n      \"pmids\": [\"31515522\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Ubap1+/E176Efx23 knock-in mice (heterozygous truncating mutation that deletes the SOUBA domain while leaving the UMA domain intact) develop progressive hind limb dysfunction, show spinal cord neuron loss and accumulation of ubiquitinated proteins, and display altered distributions of Rab5 and Rab7 in the spinal cord, indicating that UBAP1 truncation disturbs endosome-mediated vesicular trafficking in vivo.\",\n      \"method\": \"Knock-in mouse model, behavioral assays, immunohistochemistry, Rab5/Rab7 distribution analysis\",\n      \"journal\": \"Journal of human genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — in vivo knock-in model with defined molecular readouts; single lab\",\n      \"pmids\": [\"35962060\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Conditional disruption of UBAP1 in radial glial cells causes severe brain dysplasia and prenatal ventriculomegaly. UBAP1 depletion disrupts adherens junctions (AJs) and polarity of radial glial cells (RGCs), leading to failure of apically directed interkinetic nuclear migration, reduced proliferation, and precocious differentiation of neural progenitor cells. Mechanistically, UBAP1 regulates surface localization of cell adhesion molecules, and β-catenin overexpression significantly rescues Ubap1 knockdown phenotypes in vivo.\",\n      \"method\": \"Conditional knockout, in utero knockdown, immunofluorescence, live imaging, β-catenin rescue experiment\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — conditional KO with defined cellular phenotypes and genetic rescue; single lab\",\n      \"pmids\": [\"38402586\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"UBAP1 is an endosome-specific subunit of the ESCRT-I complex (together with TSG101, VPS28, and VPS37A) whose C-terminal SOUBA domain structurally binds ubiquitin through three overlapping UBA motifs, enabling ubiquitin-dependent MVB cargo sorting (e.g., EGFR, tetherin); selective assembly with VPS37A (not VPS37C) restricts its function to endosomal sorting rather than cytokinesis, and truncating mutations that abolish ubiquitin binding and endosomal targeting cause autosomal-dominant hereditary spastic paraplegia (SPG80) by disrupting endosomal trafficking, ubiquitinated protein homeostasis, and, in radial glia, adherens junction regulation during cortical neurogenesis.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"UBAP1 is an endosome-specific subunit of the ESCRT-I complex that mediates ubiquitin-dependent sorting of membrane cargo into multivesicular bodies. It assembles in a 1:1:1:1 stoichiometry with TSG101, VPS28, and selectively VPS37A (not VPS37C), restricting its function to endosomal sorting rather than cytokinesis; its C-terminal SOUBA domain, comprising three overlapping UBA motifs resolved by crystallography and NMR, independently binds ubiquitin and is required for endosomal membrane recruitment [PMID:21757351, PMID:22405001, PMID:24284069]. UBAP1 is essential for degradative sorting of receptors such as EGFR and tetherin, for endosomal ubiquitin homeostasis, and in radial glia for maintaining adherens junctions and apical polarity during cortical neurogenesis [PMID:21757351, PMID:22405001, PMID:38402586]. Heterozygous truncating mutations in UBAP1 that delete the SOUBA domain cause autosomal-dominant hereditary spastic paraplegia (SPG80), characterized by aberrant endosome morphology, cytoplasmic accumulation of ubiquitinated proteins, and progressive motor neuron degeneration [PMID:30929741, PMID:35962060].\",\n  \"teleology\": [\n    {\n      \"year\": 2011,\n      \"claim\": \"Identifying UBAP1 as an ESCRT-I subunit resolved how the endosomal ESCRT-I complex differs compositionally from the cytokinetic pool, establishing that UBAP1 confers endosome-specific cargo sorting function.\",\n      \"evidence\": \"Reciprocal co-immunoprecipitation, siRNA knockdown with EGFR sorting and ubiquitin homeostasis readouts in human cells\",\n      \"pmids\": [\"21757351\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Structural basis of UBAP1–ubiquitin interaction not yet defined\",\n        \"Why UBAP1 selects VPS37A over VPS37C not mapped\",\n        \"In vivo significance in neuronal tissues unknown\"\n      ]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Solving the SOUBA domain crystal structure revealed a unique triple-UBA solenoid architecture for ubiquitin recognition, explaining how UBAP1 captures ubiquitinated cargo and showing it is functionally required for viral exploitation of ESCRT-I (tetherin degradation by HIV-1 Vpu and KSHV K5).\",\n      \"evidence\": \"X-ray crystallography, NMR titration, reconstituted ESCRT-I complex, antiviral protein degradation assays\",\n      \"pmids\": [\"22405001\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Quantitative affinity and selectivity for different ubiquitin chain types not determined\",\n        \"Whether SOUBA domain alone is sufficient for endosomal targeting unclear\"\n      ]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Mapping the selective UBAP1–VPS37A assembly interface clarified why UBAP1 is excluded from MVB12-containing and cytokinetic ESCRT-I complexes, establishing paralog-specific functional specialization within ESCRT-I.\",\n      \"evidence\": \"Domain deletion/mutagenesis, co-immunoprecipitation, siRNA-based cargo sorting assays\",\n      \"pmids\": [\"24284069\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Atomic-resolution interface between UBAP1 and VPS37A not solved\",\n        \"Whether other post-translational modifications regulate assembly unknown\"\n      ]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Discovery that the bacterial effector PumA targets UBAP1 alongside TLR adaptors revealed a previously unrecognized connection between UBAP1/ESCRT-I and innate immune receptor trafficking.\",\n      \"evidence\": \"Co-immunoprecipitation, NF-κB reporter assays, subcellular localization of MyD88\",\n      \"pmids\": [\"28483816\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Direct binding interface between PumA and UBAP1 not mapped\",\n        \"Physiological relevance of UBAP1–MyD88 interaction in vivo not tested\",\n        \"Not independently confirmed by a second group\"\n      ]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Identification of truncating UBAP1 mutations as the cause of SPG80 established that loss of UBAP1's ubiquitin-binding and endosomal sorting function leads to human neurodegeneration, linking ESCRT-I dysfunction to hereditary spastic paraplegia.\",\n      \"evidence\": \"Whole-exome sequencing in multiple families, mRNA decay analysis, overexpression of truncated UBAP1 in HeLa/cortical neurons, in vitro ubiquitin-binding assays, zebrafish knockdown\",\n      \"pmids\": [\"30929741\", \"31203368\", \"31515522\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Whether truncated protein exerts dominant-negative or haploinsufficiency effect not resolved\",\n        \"Cell-type-specific vulnerability of upper motor neurons not explained\",\n        \"Downstream apoptotic pathways not delineated\"\n      ]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"A heterozygous knock-in mouse model recapitulated progressive motor dysfunction and spinal cord pathology of SPG80, demonstrating in vivo that SOUBA domain loss disrupts Rab5/Rab7-marked endosomal trafficking and causes ubiquitinated protein accumulation in neurons.\",\n      \"evidence\": \"Ubap1+/E176Efx23 knock-in mice, behavioral assays, immunohistochemistry, Rab distribution analysis\",\n      \"pmids\": [\"35962060\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Single lab; independent replication pending\",\n        \"Whether corticospinal tract specifically degenerates not shown\",\n        \"Temporal sequence of endosomal dysfunction versus neurodegeneration not dissected\"\n      ]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Conditional loss of UBAP1 in radial glia revealed a critical role in maintaining adherens junctions and apical-basal polarity during cortical neurogenesis, with β-catenin rescue demonstrating that UBAP1 regulates surface adhesion molecule homeostasis upstream of Wnt/β-catenin signaling.\",\n      \"evidence\": \"Conditional knockout and in utero knockdown in mouse brain, live imaging, β-catenin overexpression rescue\",\n      \"pmids\": [\"38402586\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Single lab; independent replication pending\",\n        \"Which specific adhesion molecules are UBAP1 cargo not identified\",\n        \"Whether this developmental role contributes to SPG80 disease pathogenesis not established\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"It remains unknown which specific ubiquitinated cargo proteins are sorted by UBAP1-containing ESCRT-I in motor neurons, how truncated UBAP1 protein mechanistically exerts its dominant effect, and whether therapeutic restoration of endosomal sorting can prevent SPG80 neurodegeneration.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"Neuron-specific UBAP1 cargo repertoire uncharacterized\",\n        \"Dominant-negative versus haploinsufficiency mechanism unresolved\",\n        \"No therapeutic rescue demonstrated in mammalian models\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [0, 2]},\n      {\"term_id\": \"GO:0008289\", \"supporting_discovery_ids\": [1, 5]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005768\", \"supporting_discovery_ids\": [0, 4, 5, 6]},\n      {\"term_id\": \"GO:0031410\", \"supporting_discovery_ids\": [0, 6]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-5653656\", \"supporting_discovery_ids\": [0, 1, 2, 4, 6]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [7]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [4, 6]}\n    ],\n    \"complexes\": [\n      \"ESCRT-I\"\n    ],\n    \"partners\": [\n      \"TSG101\",\n      \"VPS28\",\n      \"VPS37A\",\n      \"HDPTP\",\n      \"MYOD88\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}