Affinage

UBAP1

Ubiquitin-associated protein 1 · UniProt Q9NZ09

Length
502 aa
Mass
55.1 kDa
Annotated
2026-06-10
23 papers in source corpus 8 papers cited in narrative 8 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 8/8 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

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).

Mechanistic history

Synthesis pass · year-by-year structured walk · 8 steps
  1. 2011 High

    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

    PMID:21757351

    Open questions at the time
    • Stoichiometry and architecture of the complex not resolved
    • Structural basis of HDPTP coupling to scission not defined
  2. 2012 High

    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

    PMID:22405001

    Open questions at the time
    • Avidity/cooperativity of the three UBA motifs in cargo capture not quantified
    • How SOUBA-bound ubiquitin is handed to downstream ESCRT machinery unknown
  3. 2013 High

    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

    PMID:24284069

    Open questions at the time
    • Functional consequence of UBAP1- vs MVB12-containing ESCRT-I diversity not fully delineated
    • Cargo selectivity differences between complex variants unresolved
  4. 2017 Medium

    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

    PMID:28483816

    Open questions at the time
    • Whether UBAP1's ESCRT/ubiquitin function underlies MyD88 regulation unclear
    • Single-lab study without reciprocal in vivo validation
  5. 2019 Medium

    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

    PMID:31203368

    Open questions at the time
    • Dominant-negative versus loss-of-function contribution of truncations not fully separated
    • Mechanism linking endosome defects to apoptosis not defined
  6. 2019 Medium

    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

    PMID:31515522

    Open questions at the time
    • Contribution of partner subunits to recruitment not isolated
    • Single-lab imaging-based localization evidence
  7. 2022 Medium

    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

    PMID:35962060

    Open questions at the time
    • Causal chain from Rab dysregulation to neuron loss not established
    • Cell-type-specific vulnerability not explained
  8. 2024 Medium

    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

    PMID:38402586

    Open questions at the time
    • Whether AJ regulation reflects ESCRT-dependent sorting of adhesion molecules unproven
    • Direct molecular link between UBAP1 and β-catenin not defined

Open questions

Synthesis pass · forward-looking unresolved questions
  • 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.
  • 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

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0031386 protein tag activity 2 GO:0060090 molecular adaptor activity 2
Localization
GO:0005768 endosome 4
Pathway
R-HSA-392499 Metabolism of proteins 2 R-HSA-5653656 Vesicle-mediated transport 2
Partners
HDPTPMYD88TSG101VPS28VPS37A
Complex memberships
ESCRT-I

Evidence

Reading pass · 8 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2011 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. Co-immunoprecipitation, siRNA knockdown with functional readouts (EGFR sorting, ubiquitin homeostasis, cytokinesis assay), identification of HDPTP vs. Alix binding specificity Current biology : CB High 21757351
2012 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. 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) Structure (London, England : 1993) High 22405001
2013 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. Domain mapping by mutagenesis and co-immunoprecipitation, siRNA-mediated depletion with MVB sorting assays Journal of cell science High 24284069
2017 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. 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 The EMBO journal Medium 28483816
2019 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. 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) Brain : a journal of neurology Medium 31203368
2019 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. In vitro ubiquitin-binding assay with wild-type vs. truncated UBAP1; fluorescence microscopy of overexpressed UBAP1 variants in hippocampal neurons; endosome localization assay Journal of human genetics Medium 31515522
2022 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. Knock-in mouse model; rotarod/motor testing; histopathology; immunofluorescence for ubiquitin aggregates; Rab5/Rab7 distribution analysis Journal of human genetics Medium 35962060
2024 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. 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 Cell reports Medium 38402586

Source papers

Stage 0 corpus · 23 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2011 UBAP1 is a component of an endosome-specific ESCRT-I complex that is essential for MVB sorting. Current biology : CB 110 21757351
2012 The UBAP1 subunit of ESCRT-I interacts with ubiquitin via a SOUBA domain. Structure (London, England : 1993) 96 22405001
2019 Truncating Mutations in UBAP1 Cause Hereditary Spastic Paraplegia. American journal of human genetics 51 30929741
2019 Stop-gain mutations in UBAP1 cause pure autosomal-dominant spastic paraplegia. Brain : a journal of neurology 34 31203368
2017 A Pseudomonas aeruginosa TIR effector mediates immune evasion by targeting UBAP1 and TLR adaptors. The EMBO journal 33 28483816
2013 The molecular basis for selective assembly of the UBAP1-containing endosome-specific ESCRT-I complex. Journal of cell science 30 24284069
2001 Isolation and characterization of a novel cDNA, UBAP1, derived from the tumor suppressor locus in human chromosome 9p21-22. Journal of cancer research and clinical oncology 24 11599797
2019 UBAP1 mutations cause juvenile-onset hereditary spastic paraplegias (SPG80) and impair UBAP1 targeting to endosomes. Journal of human genetics 21 31515522
2019 Truncating variants in UBAP1 associated with childhood-onset nonsyndromic hereditary spastic paraplegia. Human mutation 18 31696996
2020 Identification of UBAP1 mutations in juvenile hereditary spastic paraplegia in the 100,000 Genomes Project. European journal of human genetics : EJHG 12 32934340
2005 Purification of novel UBAP1 protein and its decreased expression on nasopharyngeal carcinoma tissue microarray. Protein expression and purification 11 16226037
2020 Autosomal dominant hereditary spastic paraplegia caused by mutation of UBAP1. Neurogenetics 8 32222895
2022 A novel mutation in the UBAP1 gene causing hereditary spastic paraplegia: A case report and overview of the genotype-phenotype correlation. Frontiers in genetics 5 35928447
2022 Ubap1 knock-in mice reproduced the phenotype of SPG80. Journal of human genetics 5 35962060
2024 ESCRT-I protein UBAP1 controls ventricular expansion and cortical neurogenesis via modulating adherens junctions of radial glial cells. Cell reports 4 38402586
2021 Two novel truncating variants in UBAP1 are responsible for hereditary spastic paraplegia. PloS one 4 34191852
2005 [Expression and location of UBAP1 protein associated with nasopharyngeal carcinoma]. Zhong nan da xue xue bao. Yi xue ban = Journal of Central South University. Medical sciences 3 16708796
2002 [Identification of digital differential expression patterns of a novel human gene (UBAP1) by an expressed sequence tag strategy]. Ai zheng = Aizheng = Chinese journal of cancer 3 12451983
2001 Cloning and Expression Analysis of a Novel Gene, UBAP1, Possibly Involved in Ubiquitin Pathway. Sheng wu hua xue yu sheng wu wu li xue bao Acta biochimica et biophysica Sinica 3 12050802
2012 UBAP1: a new ESCRT member joins the cl_Ub. Structure (London, England : 1993) 2 22404994
2025 4-Phenylbutyric Acid Improves Gait Ability of UBAP1-Related Spastic Paraplegia Mouse Model: Therapeutic Potential for SPG80. International journal of molecular sciences 1 41097044
2022 Novel Frameshift Heterozygous Mutation in UBAP1 Gene Causing Spastic Paraplegia-80: Case Report With Literature Review. Frontiers in neurology 1 35321509
2025 Ubiquitin-Associated Protein 1 (UBAP1) Gene Mutation in a 36-Year-Old Filipino Male With Spastic Paraplegia: A Case Report. Cureus 0 39801705

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