{"gene":"UBAP1","run_date":"2026-06-10T10:51:56","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 and binds the endosomal Bro1 protein HDPTP (but not Alix). UBAP1 is required for sorting EGFR to the MVB and for endosomal ubiquitin homeostasis, but not for cytokinesis.","method":"Co-immunoprecipitation, siRNA knockdown with functional readouts (EGFR sorting, ubiquitin homeostasis, cytokinesis assay), identification of HDPTP vs. Alix binding specificity","journal":"Current biology : CB","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP, siRNA depletion with multiple orthogonal functional readouts, replicated and extended by subsequent independent studies","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 adopts a SOUBA (solenoid of overlapping UBAs) domain, in which each of three rigidly arranged overlapping UBA motifs independently interacts with ubiquitin as shown by NMR. UBAP1-containing ESCRT-I is essential for degradation of antiviral cell-surface proteins tetherin (BST-2/CD317) by HIV-1 Vpu and KSHV K5.","method":"X-ray crystallography of UBAP1 C-terminal domain, NMR analysis of ubiquitin binding by individual UBA motifs, biochemical reconstitution of 1:1:1:1 complex, siRNA knockdown functional assay (tetherin degradation)","journal":"Structure (London, England : 1993)","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structure plus NMR with functional validation, multiple orthogonal methods in one study","pmids":["22405001"],"is_preprint":false},{"year":2013,"finding":"Incorporation of UBAP1 versus MVB12A into ESCRT-I is highly selective with respect to VPS37 partners: UBAP1 selectively pairs with VPS37A. The region mediating selective assembly maps to the core ESCRT-I-binding domain of VPS37A plus a neighbouring predicted helix in VPS37A, and requires both the minimal ESCRT-I-binding region and an adjacent predicted helix in UBAP1. Functionally, siRNA depletion of UBAP1 (but not MVB12A or MVB12B) disrupts ubiquitin-dependent sorting at the MVB.","method":"Domain mapping by mutagenesis and co-immunoprecipitation, siRNA-mediated depletion with MVB sorting assays","journal":"Journal of cell science","confidence":"High","confidence_rationale":"Tier 2 / Strong — domain-mapping mutagenesis combined with reciprocal Co-IP and functional siRNA knockdown, replicated context of prior studies","pmids":["24284069"],"is_preprint":false},{"year":2017,"finding":"The Pseudomonas aeruginosa TIR effector PumA binds UBAP1 (as well as TLR adaptors TIRAP and MyD88), and UBAP1 itself can associate with MyD88, enhancing MyD88 plasma membrane localization. Combined targeting of UBAP1 and TLR adaptors by PumA impedes cytokine and TLR receptor signalling.","method":"Co-immunoprecipitation/interaction assays between PumA and UBAP1/TIRAP/MyD88; subcellular localization experiments showing UBAP1-dependent plasma membrane recruitment of MyD88; NF-κB reporter and cytokine assays","journal":"The EMBO journal","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP interaction mapping plus localization and signalling functional assays, single lab study","pmids":["28483816"],"is_preprint":false},{"year":2019,"finding":"Disease-associated truncating UBAP1 mutations result in expression of truncated proteins (escaping nonsense-mediated decay) with reduced full-length protein. Patient-derived truncated UBAP1 causes aberrant endosome clustering, pronounced endosome enlargement, and cytoplasmic accumulation of ubiquitinated proteins in HeLa cells and mouse cortical neurons. Disruption of UBAP1 leads to dysregulation of early endosome processing and ubiquitinated protein sorting, and promotes neurodegeneration potentially via apoptosis.","method":"Expression of truncated UBAP1 in HeLa cells and primary cortical neurons (immunocytochemistry, ubiquitin aggregation assay); Ubap1flox conditional knockout neurons; in vivo zebrafish Ubap1 knockdown (motor neuron morphology, mobility)","journal":"Brain : a journal of neurology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — cell-based and in vivo loss-of-function with multiple phenotypic readouts, single lab","pmids":["31203368"],"is_preprint":false},{"year":2019,"finding":"A C-terminal deletion mutant of UBAP1 (disease model) loses its ability to bind ubiquitin in vitro. Wild-type UBAP1 overexpressed in mouse hippocampal neurons interacts directly with ubiquitin on enlarged endosomes, whereas the UBAP1-mutant cannot be recruited to endosome membranes, indicating the SOUBA domain is required for endosomal targeting.","method":"In vitro ubiquitin-binding assay with wild-type vs. truncated UBAP1; fluorescence microscopy of overexpressed UBAP1 variants in hippocampal neurons; endosome localization assay","journal":"Journal of human genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vitro binding assay plus direct localization imaging in primary neurons, single lab","pmids":["31515522"],"is_preprint":false},{"year":2022,"finding":"Ubap1+/E176Efx23 knock-in mice (SOUBA domain deleted, UMA domain intact) develop progressive hind limb dysfunction, spinal cord neuron loss, accumulation of ubiquitinated proteins, and 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; rotarod/motor testing; histopathology; immunofluorescence for ubiquitin aggregates; Rab5/Rab7 distribution analysis","journal":"Journal of human genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo knock-in model with histological and trafficking readouts, single lab","pmids":["35962060"],"is_preprint":false},{"year":2024,"finding":"Conditional disruption of UBAP1 in radial glial cells (RGCs) causes severe brain dysplasia and prenatal ventriculomegaly. Mechanistically, UBAP1 regulates expression and surface localization of cell adhesion molecules, maintains adherens junctions (AJs) and polarity of RGCs, and is required for apically directed interkinetic nuclear migration. β-catenin overexpression significantly rescues the Ubap1 knockdown phenotypes in vivo, placing UBAP1 upstream of β-catenin/AJ regulation in cortical neurogenesis.","method":"Conditional knockout and shRNA knockdown in vivo; immunofluorescence for AJ markers; interkinetic nuclear migration assay; β-catenin rescue experiment; surface biotinylation for cell adhesion molecule localization","journal":"Cell reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — conditional KO with multiple cellular readouts and genetic rescue, single lab","pmids":["38402586"],"is_preprint":false}],"current_model":"UBAP1 is a subunit of an endosome-specific ESCRT-I complex (with TSG101, VPS28, and VPS37A) whose C-terminal SOUBA domain — three rigidly arranged, overlapping UBA motifs — directly binds ubiquitin to recruit ubiquitinated cargo for MVB sorting; it selectively partners with VPS37A (not VPS37C) through defined interaction surfaces, binds the endosomal Bro1 protein HDPTP to couple cargo sorting to membrane scission, and its loss or truncation disrupts endosomal ubiquitin homeostasis, causes endosome enlargement/clustering, impairs adherens-junction-dependent radial glial cell behaviour during cortical neurogenesis, and leads to neurodegeneration in neurons — with dominant-negative truncating mutations causing hereditary spastic paraplegia (SPG80)."},"narrative":{"mechanistic_narrative":"UBAP1 is a subunit of an endosome-specific ESCRT-I complex that couples recognition of ubiquitinated cargo to its sorting into multivesicular bodies (MVBs) [PMID:21757351]. It co-assembles in a stable 1:1:1:1 complex with TSG101, VPS28, and VPS37, selectively pairing with VPS37A rather than other VPS37 paralogs through defined interaction surfaces on both proteins, and its incorporation is mutually exclusive with the alternative MVB12 subunits [PMID:21757351, PMID:24284069]. Its C-terminal region forms a SOUBA domain — a solenoid of three rigidly arranged, overlapping UBA motifs that each independently bind ubiquitin — which targets the complex to endosomal membranes and is required for ubiquitin-dependent MVB sorting [PMID:22405001, PMID:31515522]. Through this activity UBAP1-containing ESCRT-I drives degradation of cell-surface cargo including EGFR and the antiviral protein tetherin (BST-2), and maintains endosomal ubiquitin homeostasis; it does not function in cytokinesis [PMID:21757351, PMID:22405001]. UBAP1 also binds the Bro1 protein HDPTP, linking cargo sorting to the membrane-scission machinery [PMID:21757351]. Loss or truncation of UBAP1 causes aberrant endosome enlargement and clustering, cytoplasmic accumulation of ubiquitinated proteins, and altered Rab5/Rab7 distribution, leading to neurodegeneration in vivo [PMID:31203368, PMID:35962060]. In developing cortex, UBAP1 maintains adherens junctions and polarity of radial glial cells upstream of β-catenin, controlling interkinetic nuclear migration during neurogenesis [PMID:38402586]. Dominant truncating mutations that delete the SOUBA domain cause hereditary spastic paraplegia (SPG80) [PMID:31203368, PMID:35962060].","teleology":[{"year":2011,"claim":"Established UBAP1 as a bona fide subunit of an endosome-specific ESCRT-I complex, defining its compositional identity and the functional branch of ESCRT it serves.","evidence":"Reciprocal Co-IP defining the TSG101/VPS28/VPS37A complex and HDPTP-binding specificity; siRNA knockdown with EGFR sorting, ubiquitin homeostasis, and cytokinesis readouts","pmids":["21757351"],"confidence":"High","gaps":["Stoichiometry and architecture of the complex not resolved","Structural basis of HDPTP coupling to scission not defined"]},{"year":2012,"claim":"Resolved the molecular basis of ubiquitin recognition by showing the C-terminal SOUBA domain uses three overlapping UBA motifs that each bind ubiquitin, and confirmed a defined 1:1:1:1 ESCRT-I stoichiometry.","evidence":"X-ray crystallography of the UBAP1 C-terminal domain, NMR of ubiquitin binding by individual UBA motifs, reconstitution of the 1:1:1:1 complex, and tetherin degradation assays","pmids":["22405001"],"confidence":"High","gaps":["Avidity/cooperativity of the three UBA motifs in cargo capture not quantified","How SOUBA-bound ubiquitin is handed to downstream ESCRT machinery unknown"]},{"year":2013,"claim":"Defined the selectivity rules of ESCRT-I assembly, showing UBAP1 pairs specifically with VPS37A through mapped interaction surfaces and that this UBAP1-specific complex is required for MVB sorting.","evidence":"Domain-mapping mutagenesis with reciprocal Co-IP and siRNA depletion in MVB sorting assays","pmids":["24284069"],"confidence":"High","gaps":["Functional consequence of UBAP1- vs MVB12-containing ESCRT-I diversity not fully delineated","Cargo selectivity differences between complex variants unresolved"]},{"year":2017,"claim":"Extended UBAP1 function beyond MVB sorting by identifying it as a host target of a bacterial TIR effector and a modulator of MyD88 plasma membrane localization and TLR/NF-κB signalling.","evidence":"Co-IP interaction mapping of PumA with UBAP1/TIRAP/MyD88, UBAP1-dependent MyD88 localization, and NF-κB reporter/cytokine assays","pmids":["28483816"],"confidence":"Medium","gaps":["Whether UBAP1's ESCRT/ubiquitin function underlies MyD88 regulation unclear","Single-lab study without reciprocal in vivo validation"]},{"year":2019,"claim":"Connected truncating UBAP1 mutations to a cellular and organismal phenotype, showing truncated protein escapes NMD and causes endosome enlargement/clustering, ubiquitin aggregation, and neurodegeneration.","evidence":"Expression of patient-derived truncations in HeLa and cortical neurons, conditional knockout neurons, and zebrafish knockdown of motor-neuron phenotypes","pmids":["31203368"],"confidence":"Medium","gaps":["Dominant-negative versus loss-of-function contribution of truncations not fully separated","Mechanism linking endosome defects to apoptosis not defined"]},{"year":2019,"claim":"Demonstrated that ubiquitin binding via the SOUBA domain is the determinant of endosomal targeting, since a C-terminal deletion abolishes both ubiquitin binding and membrane recruitment.","evidence":"In vitro ubiquitin-binding assays with WT vs truncated UBAP1 and fluorescence imaging of variants in hippocampal neurons","pmids":["31515522"],"confidence":"Medium","gaps":["Contribution of partner subunits to recruitment not isolated","Single-lab imaging-based localization evidence"]},{"year":2022,"claim":"Provided in vivo confirmation that SOUBA-deleting truncation disturbs endosomal vesicular trafficking and causes progressive motor neurodegeneration, modeling SPG80 pathology.","evidence":"Ubap1+/E176Efx23 knock-in mice with motor testing, histopathology, ubiquitin aggregate staining, and Rab5/Rab7 distribution analysis","pmids":["35962060"],"confidence":"Medium","gaps":["Causal chain from Rab dysregulation to neuron loss not established","Cell-type-specific vulnerability not explained"]},{"year":2024,"claim":"Revealed a developmental role for UBAP1 in cortical neurogenesis, placing it upstream of β-catenin in maintaining radial glial adherens junctions and interkinetic nuclear migration.","evidence":"Conditional knockout/shRNA in vivo with AJ marker imaging, surface biotinylation of adhesion molecules, interkinetic nuclear migration assay, and β-catenin rescue","pmids":["38402586"],"confidence":"Medium","gaps":["Whether AJ regulation reflects ESCRT-dependent sorting of adhesion molecules unproven","Direct molecular link between UBAP1 and β-catenin not defined"]},{"year":null,"claim":"How UBAP1-dependent endosomal sorting mechanistically connects to its developmental (β-catenin/adherens-junction) and immune (MyD88/TLR) functions, and how SOUBA truncations selectively drive neurodegeneration, remain unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unified mechanism linking cargo sorting to β-catenin signalling","Selective neuronal vulnerability to truncations unexplained","Substrate spectrum of UBAP1-ESCRT-I incompletely defined"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0031386","term_label":"protein tag activity","supporting_discovery_ids":[1,5]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[0,2]}],"localization":[{"term_id":"GO:0005768","term_label":"endosome","supporting_discovery_ids":[0,4,5,6]}],"pathway":[{"term_id":"R-HSA-5653656","term_label":"Vesicle-mediated transport","supporting_discovery_ids":[0,2]},{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[0,1]}],"complexes":["ESCRT-I"],"partners":["TSG101","VPS28","VPS37A","HDPTP","MYD88"],"other_free_text":[]}},"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":96,"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":51,"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":30,"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":21,"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":"35962060","id":"PMC_35962060","title":"Ubap1 knock-in mice reproduced the phenotype of SPG80.","date":"2022","source":"Journal of human genetics","url":"https://pubmed.ncbi.nlm.nih.gov/35962060","citation_count":5,"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 genetics","url":"https://pubmed.ncbi.nlm.nih.gov/35928447","citation_count":5,"is_preprint":false},{"pmid":"38402586","id":"PMC_38402586","title":"ESCRT-I protein UBAP1 controls ventricular expansion and cortical neurogenesis via modulating adherens junctions of radial glial cells.","date":"2024","source":"Cell reports","url":"https://pubmed.ncbi.nlm.nih.gov/38402586","citation_count":4,"is_preprint":false},{"pmid":"34191852","id":"PMC_34191852","title":"Two novel truncating variants in UBAP1 are responsible for hereditary spastic paraplegia.","date":"2021","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/34191852","citation_count":4,"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":"12451983","id":"PMC_12451983","title":"[Identification of digital 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":"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":1,"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":12376,"output_tokens":2488,"usd":0.037224,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":9695,"output_tokens":3263,"usd":0.065025,"stage2_stop_reason":"end_turn"},"total_usd":0.102249,"stage1_batch_id":"msgbatch_017qqVz33Ga63SCDwzb35XPb","stage2_batch_id":"msgbatch_01Scr2Ei9x4HJMiRGxwrmvLK","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 and binds the endosomal Bro1 protein HDPTP (but not Alix). UBAP1 is required for sorting EGFR to the MVB and for endosomal ubiquitin homeostasis, but not for cytokinesis.\",\n      \"method\": \"Co-immunoprecipitation, siRNA knockdown with functional readouts (EGFR sorting, ubiquitin homeostasis, cytokinesis assay), identification of HDPTP vs. Alix binding specificity\",\n      \"journal\": \"Current biology : CB\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP, siRNA depletion with multiple orthogonal functional readouts, replicated and extended by subsequent independent studies\",\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 adopts a SOUBA (solenoid of overlapping UBAs) domain, in which each of three rigidly arranged overlapping UBA motifs independently interacts with ubiquitin as shown by NMR. UBAP1-containing ESCRT-I is essential for degradation of antiviral cell-surface proteins tetherin (BST-2/CD317) by HIV-1 Vpu and KSHV K5.\",\n      \"method\": \"X-ray crystallography of UBAP1 C-terminal domain, NMR analysis of ubiquitin binding by individual UBA motifs, biochemical reconstitution of 1:1:1:1 complex, siRNA knockdown functional assay (tetherin degradation)\",\n      \"journal\": \"Structure (London, England : 1993)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structure plus NMR with functional validation, multiple orthogonal methods in one study\",\n      \"pmids\": [\"22405001\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Incorporation of UBAP1 versus MVB12A into ESCRT-I is highly selective with respect to VPS37 partners: UBAP1 selectively pairs with VPS37A. The region mediating selective assembly maps to the core ESCRT-I-binding domain of VPS37A plus a neighbouring predicted helix in VPS37A, and requires both the minimal ESCRT-I-binding region and an adjacent predicted helix in UBAP1. Functionally, siRNA depletion of UBAP1 (but not MVB12A or MVB12B) disrupts ubiquitin-dependent sorting at the MVB.\",\n      \"method\": \"Domain mapping by mutagenesis and co-immunoprecipitation, siRNA-mediated depletion with MVB sorting assays\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — domain-mapping mutagenesis combined with reciprocal Co-IP and functional siRNA knockdown, replicated context of prior studies\",\n      \"pmids\": [\"24284069\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"The Pseudomonas aeruginosa TIR effector PumA binds UBAP1 (as well as TLR adaptors TIRAP and MyD88), and UBAP1 itself can associate with MyD88, enhancing MyD88 plasma membrane localization. Combined targeting of UBAP1 and TLR adaptors by PumA impedes cytokine and TLR receptor signalling.\",\n      \"method\": \"Co-immunoprecipitation/interaction assays between PumA and UBAP1/TIRAP/MyD88; subcellular localization experiments showing UBAP1-dependent plasma membrane recruitment of MyD88; NF-κB reporter and cytokine assays\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP interaction mapping plus localization and signalling functional assays, single lab study\",\n      \"pmids\": [\"28483816\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Disease-associated truncating UBAP1 mutations result in expression of truncated proteins (escaping nonsense-mediated decay) with reduced full-length protein. Patient-derived truncated UBAP1 causes aberrant endosome clustering, pronounced endosome enlargement, and cytoplasmic accumulation of ubiquitinated proteins in HeLa cells and mouse cortical neurons. Disruption of UBAP1 leads to dysregulation of early endosome processing and ubiquitinated protein sorting, and promotes neurodegeneration potentially via apoptosis.\",\n      \"method\": \"Expression of truncated UBAP1 in HeLa cells and primary cortical neurons (immunocytochemistry, ubiquitin aggregation assay); Ubap1flox conditional knockout neurons; in vivo zebrafish Ubap1 knockdown (motor neuron morphology, mobility)\",\n      \"journal\": \"Brain : a journal of neurology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — cell-based and in vivo loss-of-function with multiple phenotypic readouts, single lab\",\n      \"pmids\": [\"31203368\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"A C-terminal deletion mutant of UBAP1 (disease model) loses its ability to bind ubiquitin in vitro. Wild-type UBAP1 overexpressed in mouse hippocampal neurons interacts directly with ubiquitin on enlarged endosomes, whereas the UBAP1-mutant cannot be recruited to endosome membranes, indicating the SOUBA domain is required for endosomal targeting.\",\n      \"method\": \"In vitro ubiquitin-binding assay with wild-type vs. truncated UBAP1; fluorescence microscopy of overexpressed UBAP1 variants in hippocampal neurons; endosome localization assay\",\n      \"journal\": \"Journal of human genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vitro binding assay plus direct localization imaging in primary neurons, single lab\",\n      \"pmids\": [\"31515522\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Ubap1+/E176Efx23 knock-in mice (SOUBA domain deleted, UMA domain intact) develop progressive hind limb dysfunction, spinal cord neuron loss, accumulation of ubiquitinated proteins, and 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; rotarod/motor testing; histopathology; immunofluorescence for ubiquitin aggregates; Rab5/Rab7 distribution analysis\",\n      \"journal\": \"Journal of human genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo knock-in model with histological and trafficking 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 (RGCs) causes severe brain dysplasia and prenatal ventriculomegaly. Mechanistically, UBAP1 regulates expression and surface localization of cell adhesion molecules, maintains adherens junctions (AJs) and polarity of RGCs, and is required for apically directed interkinetic nuclear migration. β-catenin overexpression significantly rescues the Ubap1 knockdown phenotypes in vivo, placing UBAP1 upstream of β-catenin/AJ regulation in cortical neurogenesis.\",\n      \"method\": \"Conditional knockout and shRNA knockdown in vivo; immunofluorescence for AJ markers; interkinetic nuclear migration assay; β-catenin rescue experiment; surface biotinylation for cell adhesion molecule localization\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — conditional KO with multiple cellular readouts and genetic rescue, single lab\",\n      \"pmids\": [\"38402586\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"UBAP1 is a subunit of an endosome-specific ESCRT-I complex (with TSG101, VPS28, and VPS37A) whose C-terminal SOUBA domain — three rigidly arranged, overlapping UBA motifs — directly binds ubiquitin to recruit ubiquitinated cargo for MVB sorting; it selectively partners with VPS37A (not VPS37C) through defined interaction surfaces, binds the endosomal Bro1 protein HDPTP to couple cargo sorting to membrane scission, and its loss or truncation disrupts endosomal ubiquitin homeostasis, causes endosome enlargement/clustering, impairs adherens-junction-dependent radial glial cell behaviour during cortical neurogenesis, and leads to neurodegeneration in neurons — with dominant-negative truncating mutations causing hereditary spastic paraplegia (SPG80).\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"UBAP1 is a subunit of an endosome-specific ESCRT-I complex that couples recognition of ubiquitinated cargo to its sorting into multivesicular bodies (MVBs) [#0]. It co-assembles in a stable 1:1:1:1 complex with TSG101, VPS28, and VPS37, selectively pairing with VPS37A rather than other VPS37 paralogs through defined interaction surfaces on both proteins, and its incorporation is mutually exclusive with the alternative MVB12 subunits [#0, #2]. Its C-terminal region forms a SOUBA domain — a solenoid of three rigidly arranged, overlapping UBA motifs that each independently bind ubiquitin — which targets the complex to endosomal membranes and is required for ubiquitin-dependent MVB sorting [#1, #5]. Through this activity UBAP1-containing ESCRT-I drives degradation of cell-surface cargo including EGFR and the antiviral protein tetherin (BST-2), and maintains endosomal ubiquitin homeostasis; it does not function in cytokinesis [#0, #1]. UBAP1 also binds the Bro1 protein HDPTP, linking cargo sorting to the membrane-scission machinery [#0]. Loss or truncation of UBAP1 causes aberrant endosome enlargement and clustering, cytoplasmic accumulation of ubiquitinated proteins, and altered Rab5/Rab7 distribution, leading to neurodegeneration in vivo [#4, #6]. In developing cortex, UBAP1 maintains adherens junctions and polarity of radial glial cells upstream of \\u03b2-catenin, controlling interkinetic nuclear migration during neurogenesis [#7]. Dominant truncating mutations that delete the SOUBA domain cause hereditary spastic paraplegia (SPG80) [#4, #6].\",\n  \"teleology\": [\n    {\n      \"year\": 2011,\n      \"claim\": \"Established UBAP1 as a bona fide subunit of an endosome-specific ESCRT-I complex, defining its compositional identity and the functional branch of ESCRT it serves.\",\n      \"evidence\": \"Reciprocal Co-IP defining the TSG101/VPS28/VPS37A complex and HDPTP-binding specificity; siRNA knockdown with EGFR sorting, ubiquitin homeostasis, and cytokinesis readouts\",\n      \"pmids\": [\"21757351\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Stoichiometry and architecture of the complex not resolved\", \"Structural basis of HDPTP coupling to scission not defined\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Resolved the molecular basis of ubiquitin recognition by showing the C-terminal SOUBA domain uses three overlapping UBA motifs that each bind ubiquitin, and confirmed a defined 1:1:1:1 ESCRT-I stoichiometry.\",\n      \"evidence\": \"X-ray crystallography of the UBAP1 C-terminal domain, NMR of ubiquitin binding by individual UBA motifs, reconstitution of the 1:1:1:1 complex, and tetherin degradation assays\",\n      \"pmids\": [\"22405001\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Avidity/cooperativity of the three UBA motifs in cargo capture not quantified\", \"How SOUBA-bound ubiquitin is handed to downstream ESCRT machinery unknown\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Defined the selectivity rules of ESCRT-I assembly, showing UBAP1 pairs specifically with VPS37A through mapped interaction surfaces and that this UBAP1-specific complex is required for MVB sorting.\",\n      \"evidence\": \"Domain-mapping mutagenesis with reciprocal Co-IP and siRNA depletion in MVB sorting assays\",\n      \"pmids\": [\"24284069\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Functional consequence of UBAP1- vs MVB12-containing ESCRT-I diversity not fully delineated\", \"Cargo selectivity differences between complex variants unresolved\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Extended UBAP1 function beyond MVB sorting by identifying it as a host target of a bacterial TIR effector and a modulator of MyD88 plasma membrane localization and TLR/NF-\\u03baB signalling.\",\n      \"evidence\": \"Co-IP interaction mapping of PumA with UBAP1/TIRAP/MyD88, UBAP1-dependent MyD88 localization, and NF-\\u03baB reporter/cytokine assays\",\n      \"pmids\": [\"28483816\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether UBAP1's ESCRT/ubiquitin function underlies MyD88 regulation unclear\", \"Single-lab study without reciprocal in vivo validation\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Connected truncating UBAP1 mutations to a cellular and organismal phenotype, showing truncated protein escapes NMD and causes endosome enlargement/clustering, ubiquitin aggregation, and neurodegeneration.\",\n      \"evidence\": \"Expression of patient-derived truncations in HeLa and cortical neurons, conditional knockout neurons, and zebrafish knockdown of motor-neuron phenotypes\",\n      \"pmids\": [\"31203368\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Dominant-negative versus loss-of-function contribution of truncations not fully separated\", \"Mechanism linking endosome defects to apoptosis not defined\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Demonstrated that ubiquitin binding via the SOUBA domain is the determinant of endosomal targeting, since a C-terminal deletion abolishes both ubiquitin binding and membrane recruitment.\",\n      \"evidence\": \"In vitro ubiquitin-binding assays with WT vs truncated UBAP1 and fluorescence imaging of variants in hippocampal neurons\",\n      \"pmids\": [\"31515522\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Contribution of partner subunits to recruitment not isolated\", \"Single-lab imaging-based localization evidence\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Provided in vivo confirmation that SOUBA-deleting truncation disturbs endosomal vesicular trafficking and causes progressive motor neurodegeneration, modeling SPG80 pathology.\",\n      \"evidence\": \"Ubap1+/E176Efx23 knock-in mice with motor testing, histopathology, ubiquitin aggregate staining, and Rab5/Rab7 distribution analysis\",\n      \"pmids\": [\"35962060\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Causal chain from Rab dysregulation to neuron loss not established\", \"Cell-type-specific vulnerability not explained\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Revealed a developmental role for UBAP1 in cortical neurogenesis, placing it upstream of \\u03b2-catenin in maintaining radial glial adherens junctions and interkinetic nuclear migration.\",\n      \"evidence\": \"Conditional knockout/shRNA in vivo with AJ marker imaging, surface biotinylation of adhesion molecules, interkinetic nuclear migration assay, and \\u03b2-catenin rescue\",\n      \"pmids\": [\"38402586\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether AJ regulation reflects ESCRT-dependent sorting of adhesion molecules unproven\", \"Direct molecular link between UBAP1 and \\u03b2-catenin not defined\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How UBAP1-dependent endosomal sorting mechanistically connects to its developmental (\\u03b2-catenin/adherens-junction) and immune (MyD88/TLR) functions, and how SOUBA truncations selectively drive neurodegeneration, remain unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unified mechanism linking cargo sorting to \\u03b2-catenin signalling\", \"Selective neuronal vulnerability to truncations unexplained\", \"Substrate spectrum of UBAP1-ESCRT-I incompletely defined\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0031386\", \"supporting_discovery_ids\": [1, 5]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [0, 2]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005768\", \"supporting_discovery_ids\": [0, 4, 5, 6]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-5653656\", \"supporting_discovery_ids\": [0, 2]},\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [0, 1]}\n    ],\n    \"complexes\": [\"ESCRT-I\"],\n    \"partners\": [\"TSG101\", \"VPS28\", \"VPS37A\", \"HDPTP\", \"MyD88\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":8,"faith_total":8,"faith_pct":100.0}}