Affinage

UBAP1

Ubiquitin-associated protein 1 · UniProt Q9NZ09

Length
502 aa
Mass
55.1 kDa
Annotated
2026-04-28
23 papers in source corpus 9 papers cited in narrative 8 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

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).

Mechanistic history

Synthesis pass · year-by-year structured walk · 7 steps
  1. 2011 High

    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

    PMID:21757351

    Open questions at the time
    • Structural basis of UBAP1–ubiquitin interaction not yet defined
    • Why UBAP1 selects VPS37A over VPS37C not mapped
    • In vivo significance in neuronal tissues unknown
  2. 2012 High

    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

    PMID:22405001

    Open questions at the time
    • Quantitative affinity and selectivity for different ubiquitin chain types not determined
    • Whether SOUBA domain alone is sufficient for endosomal targeting unclear
  3. 2013 High

    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

    PMID:24284069

    Open questions at the time
    • Atomic-resolution interface between UBAP1 and VPS37A not solved
    • Whether other post-translational modifications regulate assembly unknown
  4. 2017 Medium

    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

    PMID:28483816

    Open questions at the time
    • 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
  5. 2019 High

    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

    PMID:30929741 PMID:31203368 PMID:31515522

    Open questions at the time
    • 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
  6. 2022 Medium

    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

    PMID:35962060

    Open questions at the time
    • Single lab; independent replication pending
    • Whether corticospinal tract specifically degenerates not shown
    • Temporal sequence of endosomal dysfunction versus neurodegeneration not dissected
  7. 2024 Medium

    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

    PMID:38402586

    Open questions at the time
    • 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

Open questions

Synthesis pass · forward-looking unresolved questions
  • 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.
  • Neuron-specific UBAP1 cargo repertoire uncharacterized
  • Dominant-negative versus haploinsufficiency mechanism unresolved
  • No therapeutic rescue demonstrated in mammalian models

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0008289 lipid binding 2 GO:0060090 molecular adaptor activity 2
Localization
GO:0005768 endosome 4 GO:0031410 cytoplasmic vesicle 2
Pathway
R-HSA-5653656 Vesicle-mediated transport 5 R-HSA-1643685 Disease 2 R-HSA-1266738 Developmental Biology 1
Partners
HDPTPMYOD88TSG101VPS28VPS37A
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, 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. Co-immunoprecipitation, siRNA knockdown, subcellular fractionation, fluorescence microscopy, functional sorting assays 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 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. X-ray crystallography, NMR analysis, biochemical reconstitution, functional assays (antiviral protein degradation) Structure (London, England : 1993) High 22405001
2013 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. Domain mapping by mutagenesis, siRNA knockdown, co-immunoprecipitation, ubiquitin-dependent cargo sorting assays Journal of cell science High 24284069
2017 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. Co-immunoprecipitation, pulldown, subcellular localization assays, NF-κB reporter assays The EMBO journal Medium 28483816
2019 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. Whole-exome sequencing, mRNA decay analysis, overexpression of truncated UBAP1 in HeLa cells and cortical neurons, immunocytochemistry, zebrafish knockdown American journal of human genetics / Brain : a journal of neurology High 30929741 31203368 31515522
2019 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. In vitro ubiquitin-binding assay, overexpression in primary neurons, fluorescence microscopy Journal of human genetics Medium 31515522
2022 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. Knock-in mouse model, behavioral assays, immunohistochemistry, Rab5/Rab7 distribution analysis Journal of human genetics Medium 35962060
2024 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. Conditional knockout, in utero knockdown, immunofluorescence, live imaging, β-catenin rescue experiment 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) 95 22405001
2019 Truncating Mutations in UBAP1 Cause Hereditary Spastic Paraplegia. American journal of human genetics 50 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 29 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 20 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
2024 ESCRT-I protein UBAP1 controls ventricular expansion and cortical neurogenesis via modulating adherens junctions of radial glial cells. Cell reports 4 38402586
2022 Ubap1 knock-in mice reproduced the phenotype of SPG80. Journal of human genetics 4 35962060
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
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
2025 4-Phenylbutyric Acid Improves Gait Ability of UBAP1-Related Spastic Paraplegia Mouse Model: Therapeutic Potential for SPG80. International journal of molecular sciences 0 41097044