BLTP1, formerly KIAA1109, is a large bridge-like lipid transfer protein involved in membrane lipid homeostasis. Its conserved repeating beta-groove architecture forms a hydrophobic route for phospholipid movement between membranes. Evidence from yeast Csf1 and animal orthologs supports phosphatidylethanolamine supply and an ER-associated membrane-bridging function; human cell studies connect BLTP1 to ER–plasma-membrane contact maintenance, endosomal trafficking, recycling and phagocytic uptake. The detailed lipid-transfer mechanism and topology are established principally in orthologs. Biallelic pathogenic variants cause Alkuraya-Kucinskas syndrome, a developmental disorder with brain malformations and arthrogryposis.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0001558 regulation of cell growth | NAS PMID:17190194 Molecular cloning and preliminary analysis of a fragile site... | UNDECIDED | Summary: The older FSA study associates expression with epithelial growth and differentiation. Reason: The accessible abstract and publisher first page describe cloning, RT-PCR and immunohistochemical expression in differentiated epithelial compartments. Expression correlation does not itself demonstrate regulation of cell growth. However, the remaining methods and results of the seven-page paper could not be inspected, so the structured abstract is not treated as an exhaustive inventory of its experiments. This NAS assertion remains UNDECIDED because the evidence needed to adjudicate the regulatory claim is inaccessible; no experimental evidence code or curator full-text finding is presumed. Supporting Evidence: |
| GO:0005515 protein binding | IPI PMID:20195357 A comprehensive resource of interacting protein regions for ... | MODIFY | Summary: The curated interaction can be specified as beta-catenin binding. Reason: GOA names UniProtKB:P35222 as the interaction partner, and the normal UniProt interaction record independently identifies CTNNB1. GO:0008013 specifies beta-catenin binding without implying transcriptional regulation or Wnt signaling. The cited paper used fragment-based mRNA display. An author-attributed Table S5 mirror corroborates CTNNB1–KIAA1109 fragment pairs, but original XLS bytes, current isoform mapping and pair-specific reciprocal validation were not inspected. Neither the fragment coordinates nor NbExp=2 establish a native full-length complex or two independent studies. The interaction remains outside the core lipid-transfer synthesis. Proposed replacements: beta-catenin binding Supporting Evidence: |
| GO:0005634 nucleus | NAS PMID:17190194 Molecular cloning and preliminary analysis of a fragile site... | UNDECIDED | Summary: Nuclear localization is a historical NAS assertion whose supporting detail is unresolved. Reason: The accessible FSA abstract and publisher first page do not describe the evidence for nuclear localization. Modern UniProt topology and worm LPD-3 structural evidence instead support a single-pass ER anchor with a large cytosolic lipid-transfer bridge, making a general nucleoplasmic assignment difficult to reconcile with the established full-length protein. That architectural tension does not exclude a distinct isoform, processed fragment or specialized localization. The complete older localization results and antibody details remain inaccessible, so this historical NAS claim remains UNDECIDED rather than being rejected from an abstract alone. |
| GO:0005789 endoplasmic reticulum membrane | IEA GO_REF:0000044 | ACCEPT | Summary: BLTP1 has a conserved ER-associated membrane-bridging architecture. Reason: The IEA mapping reflects UniProt localization inferred from the worm ortholog. This is compatible with the conserved ER anchor and human BLTP1-dependent ER–plasma-membrane junction phenotype. The inference is retained as inference, without attributing a worm structural or localization assay to human BLTP1. |
| GO:0005886 plasma membrane | IEA GO_REF:0000044 | KEEP AS NON CORE | Summary: Plasma-membrane association is consistent with the conserved lipid-transfer bridge. Reason: This vocabulary-derived annotation reflects membrane association inferred from orthologs, including yeast Csf1. Human knockdown effects on contact-site abundance corroborate function but do not directly image endogenous human BLTP1. Retain the broad plasma-membrane association as non-core, consistently with the specialized apical-membrane inference; the core locations explicitly identify the ER anchor and ER–plasma-membrane contact site. |
| GO:0005886 plasma membrane | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: The yeast ortholog supports plasma-membrane association by similarity. Reason: The named donor Q12150 is yeast Csf1, not the unrelated human CSF1 cytokine. Its contact-site membrane association supports retaining the ISS annotation with its organism boundary. The broad plasma-membrane term is non-core; the synthesis specifies the ER anchor and intermembrane contact rather than promoting the donor localization to a direct human observation. |
| GO:0006909 phagocytosis | IMP PMID:31540829 Systematic Identification of Host Cell Regulators of Legione... | KEEP AS NON CORE | Summary: Human KIAA1109 perturbation impairs phagocytic uptake in U937 cells. Reason: Two independent sgRNAs reduced uptake of nonpathogenic delta-dotA Legionella in the cited study. This supports the existing IMP process annotation. Phagocytic uptake is a cellular consequence of BLTP1 function rather than a separate demonstrated molecular activity. Broader substrate, mouse-cell and rescue experiments in the same paper primarily concern C1orf43 and are not assigned to BLTP1. Supporting Evidence: PMID:31540829 knockouts of the uncharacterized genes C1orf43 and KIAA1109 significantly impaired phagocytosis of L. pneumophila |
| GO:0015914 phospholipid transport | IEA GO_REF:0000108 | ACCEPT | Summary: Phospholipid transport captures the central biological role of the lipid-transfer bridge. Reason: The logical inference from phosphatidylethanolamine transfer activity is appropriate. Conserved architecture and ortholog experiments support membrane lipid movement. The generic process is retained alongside the more explicit existing intermembrane-transfer assertion without manufacturing a second activity. |
| GO:0016020 membrane | NAS PMID:16632497 G8: a novel domain associated with polycystic kidney disease... | KEEP AS NON CORE | Summary: Broad membrane association is consistent with the established protein family. Reason: The original G8-domain paper provides historical sequence-based context rather than a direct BLTP1 localization assay. Modern bridge-like lipid-transfer evidence independently supports membrane association. Retain this accurate but broad term as non-core because the ER-membrane and ER–plasma-membrane-contact-site terms already express the informative locations of the core mechanism. |
| GO:0016197 endosomal transport | IMP PMID:30906834 Endosomal trafficking defects in patient cells with KIAA1109... | KEEP AS NON CORE | Summary: Patient fibroblasts with biallelic KIAA1109 variants show endosomal trafficking defects. Reason: The cited study compares cells from one affected individual with a healthy donor and reports altered endosomal markers and dextran trafficking. This supports retaining the experimental annotation while distinguishing the cellular phenotype from the conserved lipid-transfer molecular activity. The inspected results do not establish direct BLTP1 localization to every affected endosomal compartment or a genetic rescue. Supporting Evidence: PMID:30906834 with an accumulation of dextran in the patient cells |
| GO:0016324 apical plasma membrane | IEA GO_REF:0000044 | KEEP AS NON CORE | Summary: Apical membrane association is supported by ortholog-based localization inference. Reason: The UniProt mapping traces to worm LPD-3 at an apical membrane contact. Retain the curated inference as a specialized epithelial context rather than claiming directly established polarity-specific localization of human BLTP1 or a universal core compartment. Supporting Evidence: |
| GO:0030856 regulation of epithelial cell differentiation | NAS PMID:17190194 Molecular cloning and preliminary analysis of a fragile site... | UNDECIDED | Summary: The early FSA expression study proposed a role in epithelial differentiation. Reason: The accessible abstract and publisher first page show expression associated with postmitotic differentiated epithelia and an authors’ proposed regulatory role. Expression in differentiated cells alone does not establish that BLTP1 regulates their differentiation. The rest of the paper remains inaccessible, and its structured abstract cannot establish that no additional functional experiment exists. Keep this NAS assertion UNDECIDED until the supporting results can be assessed. Supporting Evidence: |
| GO:0031966 mitochondrial membrane | IEA GO_REF:0000044 | KEEP AS NON CORE | Summary: Mitochondrial membrane association is an ortholog-derived localization claim. Reason: This electronic mapping follows UniProt similarity evidence from yeast Csf1. Retain its limited evolutionary inference without promoting it to directly measured human localization or a demonstrated central human mitochondrial role. The principal mechanistic synthesis is ER-associated intermembrane lipid transfer. In the yeast work, localization near ER–mitochondrial contacts must be distinguished from direct human mitochondrial targeting or membrane insertion. Supporting Evidence: |
| GO:0031966 mitochondrial membrane | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: The yeast Csf1 donor supports a mitochondrial membrane association by similarity. Reason: The source is Q12150, the yeast bridge-like lipid-transfer protein. Keep the ISS assertion with that organism boundary explicit; the inspected human studies do not directly establish mitochondrial localization. Lack of a human experiment alone is not evidence that the curator’s transfer is wrong. In the yeast work, localization near ER–mitochondrial contacts must be distinguished from direct human mitochondrial targeting or membrane insertion. Supporting Evidence: |
| GO:0032456 endocytic recycling | IMP PMID:30906834 Endosomal trafficking defects in patient cells with KIAA1109... | KEEP AS NON CORE | Summary: Endocytic recycling is perturbed in the patient-cell study. Reason: Altered Rab4/Rab11-associated trafficking and dextran pulse-chase behavior support the existing IMP annotation. Recycling is an important cellular context for membrane lipid homeostasis, but these experiments do not identify an additional BLTP1 catalytic or adaptor activity. Supporting Evidence: |
| GO:0048488 synaptic vesicle endocytosis | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: The PAINT inference assigns a conserved synaptic-vesicle endocytosis role. Reason: The fly descendant and ancestral node PTN000781310 are part of a curator-mediated phylogenetic inference. A single listed donor is not weak or circular evidence. No target-specific loss or incompatible phylogenetic placement has been established, so retain the process as a neuronal context; a complete tree and alignment audit is not claimed. Supporting Evidence: GO_REF:0000033 |
| GO:0098793 presynapse | IEA GO_REF:0000108 | KEEP AS NON CORE | Summary: Presynaptic localization is inferred from the synaptic-vesicle-endocytosis process. Reason: This is a logical inter-ontology inference, not a separate localization experiment. Retain it consistently with the preserved PAINT process annotation while keeping the neuronal context outside the general lipid-transfer core. Supporting Evidence: GO_REF:0000108 GO_REF:0000033 |
| GO:0120009 intermembrane lipid transfer | ISS GO_REF:0000024 | ACCEPT | Summary: Intermembrane lipid transfer captures the conserved bridge mechanism. Reason: Yeast Csf1 and animal ortholog evidence supports lipid movement between membrane surfaces through a large hydrophobic bridge. This is a biological process term; it must not be placed in the molecular-function slot. The human assignment remains an orthology-based inference. |
| GO:0140268 endoplasmic reticulum-plasma membrane contact site | ISS GO_REF:0000024 | ACCEPT | Summary: ER–plasma-membrane contact sites provide a conserved setting for BLTP1 lipid transfer. Reason: The existing ISS assertion is supported by yeast and worm ortholog context. Human BLTP1 knockdown reduces GFP-MAPPER-marked contacts, supporting a role in their maintenance without independently demonstrating direct human BLTP1 localization at every contact. |
| GO:1904121 phosphatidylethanolamine transfer activity | ISS GO_REF:0000024 | MODIFY | Summary: The conserved transfer activity is supported more securely than phosphatidylethanolamine specificity. Reason: The donor is yeast Csf1. PMID35015055 links it to phosphatidylethanolamine availability for GPI-anchor synthesis but explicitly allows transport of another lipid or indirect regulation of Mcd4. In PMID40269155, the native worm LPD-3 structure contains phospholipid-like densities whose precise chemical identities were unresolved; modeling them as phosphoethanolamine does not establish substrate selectivity. These source-specific limits support replacing the PE-specific activity with GO:0120014 phospholipid transfer activity, consistently with the conserved bridge architecture and the core synthesis. The human assignment remains an orthology-based inference, not a purified human substrate-selectivity measurement or GPI-anchor biosynthetic catalysis. No redundant NEW ancestor annotation is added. Proposed replacements: phospholipid transfer activity Supporting Evidence: PMID:35015055 we cannot rule out that Csf1 indirectly affects GPI anchor synthesis by transporting another lipid PMID:40269155 As the resolution of the lipid densities was insufficient to determine their precise identity |
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Download this section (compressed HTML)Q: Which lipids are transferred by purified human BLTP1, and how does its substrate preference compare with yeast Csf1 and worm LPD-3?
Q: Which human BLTP1 isoforms form functional ER–plasma-membrane bridges with LTAP1/C1orf43 and other accessory proteins? UniProt infers direct LTAP1 association from the worm LPD-3–Spigot complex; the native human complex composition and stoichiometry remain to be established.
Q: What experiments in the original FSA study support nuclear localization and direct regulation of epithelial growth or differentiation?
Q: What functional role, if any, does the curated BLTP1–beta-catenin interaction play beyond physical association?
Q: How do the actin and ciliary abnormalities in patient fibroblasts relate to defective lipid transfer and membrane trafficking, and which phenotypes are corrected by complementation with human BLTP1?
Experiment: Reconstitute human BLTP1 with defined donor and acceptor membranes and candidate accessory proteins, measuring transfer of multiple phospholipid classes and distinguishing transport from membrane tethering.
Hypothesis: Human BLTP1 transfers phospholipids through a conserved bridge, but its substrate preference remains unresolved.
Experiment: Use endogenous human BLTP1 tagging and loss-of-function complementation to link contact-site localization and lipid flux to endosomal recycling, without inferring localization from altered compartment markers alone.
Hypothesis: A conserved ER-associated bridge supports membrane trafficking through lipid supply and contact maintenance.
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