{"gene":"VPS13A","run_date":"2026-06-11T09:02:06","timeline":{"discoveries":[{"year":2018,"finding":"The N-terminal portion of VPS13A forms a tubular structure with a hydrophobic cavity that can solubilize and transport glycerolipids between membranes in vitro. VPS13A binds to the ER and tethers it to mitochondria and lipid droplets, functioning as a lipid transporter at ER-organelle membrane contact sites.","method":"In vitro lipid transport reconstitution assay, structural analysis of N-terminal domain, subcellular fractionation and co-localization imaging","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro reconstitution of lipid transport, structural characterization, multiple orthogonal methods in a single rigorous study, widely replicated concept","pmids":["30093493"],"is_preprint":false},{"year":2019,"finding":"VPS13A is a peripheral membrane protein localized at ER-mitochondria contact sites, lipid droplets, and the ER. It interacts with the ER-resident protein VAP-A via its FFAT domain, and its C-terminal domain mediates interaction with mitochondria. VPS13A depletion decreases ER-mitochondria contact sites, causes mitochondrial fragmentation, decreases mitophagy, and increases lipid droplet numbers.","method":"Co-immunoprecipitation (VAP-A interaction via FFAT domain), domain truncation mapping (C-terminal mitochondrial interaction), live-cell imaging, siRNA knockdown with quantitative phenotypic readouts","journal":"eLife","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP, domain mapping, live-cell imaging, multiple orthogonal methods with clean loss-of-function phenotypes","pmids":["30741634"],"is_preprint":false},{"year":2015,"finding":"VPS13A (via its Dictyostelium ortholog TipC) is required for autophagy. TipC/VPS13A-null cells show a reduced number of autophagosomes and impaired autophagic flux. The C-terminal region containing the ATG2-homology domain and DUF1162 is sufficient to complement the mutant phenotype. Human VPS13A knockdown in HeLa cells also causes accumulation of autophagic markers and impaired autophagic flux.","method":"Genetic knockout in Dictyostelium, GFP-Atg18 and GFP-Atg8 autophagosome markers, proteolytic cleavage autophagic flux assay, domain complementation, siRNA knockdown in HeLa cells","journal":"Autophagy","confidence":"High","confidence_rationale":"Tier 2 / Strong — clean KO with defined cellular phenotype, domain rescue, confirmed in two model systems (Dictyostelium and human cells)","pmids":["25996471"],"is_preprint":false},{"year":2019,"finding":"VPS13A interacts with RAB7A (a key endosomal trafficking regulator) in both Dictyostelium and human HeLa cells. Loss of VPS13A impairs endocytic trafficking and lysosomal degradation, and disrupts membrane contact sites between mitochondria-endosomes and mitochondria-ER.","method":"Co-immunoprecipitation of VPS13A and RAB7A in HeLa cells, Dictyostelium genetic studies, endolysosomal marker analysis","journal":"Disease models & mechanisms","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — Co-IP interaction confirmed in two species, loss-of-function phenotype with lysosomal markers, single lab","pmids":["30709847"],"is_preprint":false},{"year":2020,"finding":"XK forms a protein complex with VPS13A in human cells. Overexpressed XK relocalizes VPS13A from lipid droplets to subdomains of the ER. Two ChAc disease-linked missense mutations in VPS13A prevent this XK-induced relocalization, suggesting XK is a partner that recruits VPS13A to specific contact sites.","method":"Co-immunoprecipitation in human cells, overexpression relocalization assay, disease-mutant VPS13A analysis","journal":"Molecular biology of the cell","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP, functional relocalization assay with disease mutations, single lab","pmids":["32845802"],"is_preprint":false},{"year":2022,"finding":"VPS13A localizes at ER-plasma membrane (ER-PM) contact sites via binding of its PH domain to a cytosolic loop of the lipid scramblase XK. This interaction is regulated by an intramolecular interaction within XK. Binding of the VPS13A PH domain to XK is competitive with its binding to intracellular membranes mediating other tethering functions. Both VPS13A and XK are highly expressed in caudate neurons.","method":"Co-localization imaging, domain-level binding assays (PH domain), AlphaFold structural modeling, competitive binding assays, cell-type expression analysis","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 / Strong — domain-level interaction mapping, structural modeling with functional validation, competitive binding assays, multiple orthogonal methods","pmids":["35994651"],"is_preprint":false},{"year":2022,"finding":"In mouse T cells, VPS13A and XK form a complex at the plasma membrane (confirmed by blue-native PAGE) and are essential for P2X7 receptor-mediated phosphatidylserine exposure, phosphatidylcholine internalization, and necrotic cell death in response to extracellular ATP. Null mutation in either Xk or Vps13a blocks these processes.","method":"CRISPR/Cas9 genome-wide screen, blue-native PAGE (complex detection), phospholipid scrambling assays (annexin V/PtdSer exposure), cell lysis assay, T cell transformation system","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — CRISPR screen plus native PAGE complex confirmation, multiple functional readouts (PtdSer exposure, lipid internalization, cell lysis), clean null mutant phenotypes","pmids":["35140185"],"is_preprint":false},{"year":2022,"finding":"The pleckstrin homology (PH) domain at the C-terminal region of VPS13A is required for complex formation with XK and for co-localization of VPS13A with XK within the cell. AlphaFold modeling predicted an interaction surface between VPS13A and XK; mutations at this interface disrupt both complex formation and co-localization. Disease-causing truncating mutations in VPS13A patients remove the PH domain.","method":"Domain mutagenesis, co-immunoprecipitation, co-localization imaging, AlphaFold structural modeling","journal":"Journal of cell science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — domain mutagenesis plus Co-IP and localization, single lab, structural modeling not experimentally validated by crystallography","pmids":["35950506"],"is_preprint":false},{"year":2023,"finding":"The sorting nexin SNX5 interacts with VPS13A and mediates its association with endosomal subdomains. This interaction involves the VPS13 adaptor-binding (VAB) domain of VPS13A and a PxP motif in SNX5. Mutation of a conserved asparagine in the VAB domain (also pathogenic in VPS13D) impairs this interaction. VPS13A C-terminal domain directs localization to mitochondria, while VAB-domain-containing fragments co-localize with SNX5 at endosomes.","method":"Co-immunoprecipitation, domain truncation/mutation analysis, co-localization imaging, yeast comparative genetics","journal":"Life science alliance","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP plus domain mapping with mutagenesis, single lab, supported by yeast comparative data","pmids":["36977596"],"is_preprint":false},{"year":2023,"finding":"VPS13A directly interacts with ATG9A (the autophagy transmembrane lipid scramblase) and forms a complex distinct from the ATG9A-ATG2A complex, as revealed by mass spectrometry-based interactome analysis and validated biochemically.","method":"Immunoprecipitation mass spectrometry (interactome), biochemical complex validation","journal":"Journal of cell science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — IP-MS interactome with biochemical validation of distinct complex, single lab","pmids":["38294121"],"is_preprint":false},{"year":2023,"finding":"VPS13A interaction with XK at ER-PM contacts is cell-type/state dependent. In hemin-differentiated K562 erythroblast-like cells, tagged VPS13A robustly forms ER-PM contacts that require XK (abolished in XK KO cells). In undifferentiated K562 cells, despite similar XK levels, ER-PM contacts are rarely observed, indicating a permissive cellular state is required.","method":"Overexpression co-localization imaging in K562 cells ± hemin differentiation, XK CRISPR KO, quantitative contact site analysis","journal":"Contact (Thousand Oaks (Ventura County, Calif.))","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — clean KO with quantitative imaging phenotype, two cell states compared, single lab","pmids":["38144430"],"is_preprint":false},{"year":2022,"finding":"Loss of VPS13A (or VPS13C) in U-2 OS cells results in reduced lipid droplet abundance under oleate-stimulated conditions, implicating VPS13A in lipid droplet regulation at ER-lipid droplet contact sites.","method":"CRISPR-Cas9 knockout (exon 2 deletion/frameshift), lipid droplet quantification under oleate stimulation","journal":"Contact (Thousand Oaks (Ventura County, Calif.))","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — clean CRISPR KO with defined phenotypic readout, single lab, single method","pmids":["36147729"],"is_preprint":false},{"year":2012,"finding":"In differentiated PC12 cells, VPS13A (chorein) localizes to dense-core vesicles (DCVs) containing dopamine and co-localizes with synaptotagmin I at neurite termini. Stable expression of the C-terminal fragment of chorein increases K+-induced dopamine release, suggesting VPS13A is involved in exocytosis of DCVs.","method":"Immunocytochemistry, sucrose density gradient fractionation, dopamine release assay (K+-stimulated exocytosis), stable overexpression","journal":"Biochemical and biophysical research communications","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, partial mechanistic follow-up, C-terminal fragment overexpression effect without full loss-of-function validation","pmids":["22366033"],"is_preprint":false},{"year":2020,"finding":"VPS13A and VPS13C interact with TBC1D1 (a Rab-GTPase activating protein) in C2C12 myotubes via TBC1D1's phosphotyrosine binding (PTB) domains. Depletion of VPS13A causes a post-transcriptional increase in cellular GLUT4 protein and enhanced cell-surface GLUT4 upon AMPK activation, specifically affecting GLUT4 homeostasis.","method":"Quantitative proteomics (unbiased Co-IP-MS), domain mapping, siRNA depletion, GLUT4 cell-surface assay (AMPK-stimulated)","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — unbiased MS interactome plus functional depletion phenotype with specific GLUT4 readout, single lab","pmids":["33087848"],"is_preprint":false},{"year":2015,"finding":"VPS13A (chorein) promotes PI3K activation and supports cell survival signaling: siRNA silencing in rhabdomyosarcoma cells reduces phosphorylated PI3K, downregulates BCL-2, upregulates BAX, causes mitochondrial depolarization, caspase-3 activation, and apoptosis.","method":"siRNA silencing, Western blot (phospho-PI3K, BCL-2, BAX), FACS apoptosis analysis, mitochondrial membrane potential assay","journal":"Oncotarget","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, single depletion approach, cancer cell line context with no pathway placement beyond correlation","pmids":["25871399"],"is_preprint":false},{"year":2025,"finding":"Absence of VPS13A impairs autophagy in skeletal muscle, leading to pathologic metabolic remodeling, increased protein/lipid oxidation, defects in myofibril stability, and accumulation of the senescence marker NCAM1 in Vps13a-/- mice. Rapamycin treatment rescued accumulation of LAMP1, p62, and NCAM1, linking impaired autophagy to accelerated aging in the absence of VPS13A.","method":"Vps13a-/- mouse model, starvation/colchicine autophagy assay, rapamycin rescue, patient muscle biopsies, proteomics, immunohistochemistry","journal":"Acta neuropathologica communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — mouse KO plus human biopsy validation, rapamycin rescue provides mechanistic link, multiple readouts, single lab","pmids":["40275365"],"is_preprint":false},{"year":2023,"finding":"VPS13A knockdown in cortical neurons and striatum of mice increases DAG species, reduces PKCβII concentration while increasing PKCα/βII phosphorylation, and causes increased neuronal branching, decreased BDNF and PSD-95, impaired corticostriatal long-term depression (LTD), and hyperlocomotion. Pharmacological inhibition of PKCβII rescues aberrant neuronal morphology and spine density loss.","method":"Lipidomics (DAG quantification), Western blot (PKC isoforms and phosphorylation), AAV-mediated VPS13A knockdown in vivo, electrophysiology (LTD), behavioral assays, pharmacological rescue (PKCβII inhibitor)","journal":"BMC biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo KD with lipidomics plus electrophysiology and pharmacological rescue, single lab, multiple orthogonal methods","pmids":["42237281"],"is_preprint":false},{"year":2026,"finding":"Cryo-EM structure of VPS13A complexed with the scramblase XKR1 at near-atomic resolution shows that VPS13A interacts with XKR1 via its PH domain, orienting VPS13A's lipid-transfer domain to deliver lipids to the cytosolic leaflet of the acceptor membrane. Molecular dynamics simulations confirm robust lipid transfer in this configuration, with scramblase activity allowing equilibration of newly transferred lipids between membrane leaflets.","method":"Cryo-electron microscopy (near-atomic resolution), molecular dynamics simulations","journal":"bioRxiv","confidence":"High","confidence_rationale":"Tier 1 / Moderate — cryo-EM structure plus MD simulations in a single study; preprint but provides direct structural mechanism","pmids":["41542425"],"is_preprint":true},{"year":2026,"finding":"Mutational analysis of the VPS13A-XK interaction interface revealed that VPS13A binds XK through a C-terminal β-strand that interacts with a β-hairpin in the central region of XK, and this interaction is essential for scramblase activity. Ten patient-derived VPS13A variants were classified into four functional groups: (a) reduced expression (L67P, I90K, W2453R); (b) normal expression but absent scramblase activity (A1091P, M3080R); (c) modest impairment of expression or activity; and (d) a gain-of-function variant (I2763R) that alters cell size and disrupts ER independently of XK. XKR2, a XK paralog with a similar β-hairpin, also associates with VPS13A and supports phospholipid scrambling.","method":"Site-directed mutagenesis, phospholipid scrambling functional assay, Western blot (expression), cell morphology analysis, mouse cell expression system","journal":"The Journal of clinical investigation","confidence":"High","confidence_rationale":"Tier 1 / Moderate — reconstitution plus mutagenesis with functional assay, systematic characterization of disease mutations, single lab but multiple orthogonal methods","pmids":["41874565"],"is_preprint":false},{"year":2026,"finding":"Loss of VPS13A in patient-derived fibroblasts causes impaired lipid transfer into mitochondria, reduced lipid droplet formation, disturbance of membrane contact sites, and unusual mitochondrial calcium uptake behavior, as demonstrated by labeled fatty acid tracking and mitochondrial calcium indicator assays.","method":"Labeled fatty acid transfer assay, mitochondrial calcium indicator (Rhod-2 AM), super-resolution microscopy (Airyscan2), VPS13A-deficient patient fibroblasts vs. healthy controls","journal":"Movement disorders","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — patient fibroblasts with labeled lipid tracking and calcium assays plus super-resolution imaging, single lab","pmids":["41552990"],"is_preprint":false},{"year":2025,"finding":"VPS13A and VPS13C have partially redundant lipid transfer functions: single Vps13a or Vps13c KO mice are viable, but double KO (DKO) mice die at midgestation with defective erythropoiesis, innate immune activation (upregulation of ISGs, RIG-I, MDA5), suggesting that combined loss of lipid flux from both proteins causes loss of organelle membrane integrity.","method":"Vps13a/Vps13c double knockout mouse, embryonic phenotyping, erythroid differentiation assays, innate immunity gene expression profiling","journal":"PLoS biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic epistasis via double KO with clear embryonic lethal phenotype and molecular readouts, published peer-reviewed and replicated in preprint","pmids":["40956846"],"is_preprint":false},{"year":2026,"finding":"ATG9A lipid scramblase activity and VPS13A lipid transfer protein activity are both required for efficient plasma membrane repair in mammalian cells.","method":"Plasma membrane damage assay, genetic knockdown/KO of ATG9A and VPS13A, functional complementation","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — clean KO/KD with defined functional readout (membrane repair), single lab, ATG9A-VPS13A functional epistasis","pmids":["42044337"],"is_preprint":false}],"current_model":"VPS13A (chorein) is a bridge-like bulk lipid transfer protein that localizes at multiple ER-organelle membrane contact sites (ER-mitochondria, ER-lipid droplets, ER-endosomes, ER-plasma membrane), where it transports glycerolipids through a hydrophobic tubular channel formed by its N-terminal domain; it is recruited to specific contact sites via adaptor interactions—including binding of its FFAT domain to VAP-A (ER), its C-terminal domain to mitochondria, its VAB domain to SNX5 (endosomes), and its PH domain to the lipid scramblase XK (plasma membrane)—and the VPS13A-XK complex is essential for P2X7-stimulated phosphatidylserine scrambling and necrotic cell death in T cells, with loss of VPS13A impairing ER-mitochondria contacts, mitochondrial morphology, lipid droplet homeostasis, lysosomal degradation, autophagy, and DAG/PKC-mediated neuronal signaling."},"narrative":{"mechanistic_narrative":"VPS13A (chorein) is a bridge-like bulk lipid transfer protein that moves glycerolipids between organelle membranes at ER-organelle contact sites, with its N-terminal domain forming a hydrophobic tubular channel that solubilizes and shuttles lipids in vitro [PMID:30093493]. It is recruited to distinct contact sites through modular adaptor interactions: an FFAT-mediated interaction with the ER protein VAP-A and a C-terminal domain that engages mitochondria [PMID:30741634], a VAB domain that binds a PxP motif in SNX5 at endosomal subdomains [PMID:36977596], and a C-terminal PH domain that binds a cytosolic loop of the plasma-membrane lipid scramblase XK in a manner competitive with its other membrane-tethering activities [PMID:35994651]. The VPS13A-XK complex pairs lipid transfer with scramblase activity to deliver and equilibrate lipids across membrane leaflets [PMID:41542425], and this complex is essential for P2X7-stimulated phosphatidylserine exposure and necrotic cell death in T cells [PMID:35140185]; the C-terminal β-strand of VPS13A docks into a β-hairpin of XK, an interface required for scramblase function and disrupted by patient-derived variants [PMID:41874565]. Through these contacts VPS13A maintains ER-mitochondria tethering, mitochondrial morphology and lipid import, and lipid droplet homeostasis, and its loss fragments mitochondria and perturbs lipid droplet abundance [PMID:30741634, PMID:36147729, PMID:41552990]. VPS13A also supports autophagy and autophagic flux—acting in part through a direct interaction with the lipid scramblase ATG9A [PMID:25996471, PMID:38294121]—and contributes to endolysosomal trafficking via RAB7A [PMID:30709847] and to plasma membrane repair together with ATG9A [PMID:42044337]. VPS13A and the paralog VPS13C are partially redundant, since combined loss is embryonic lethal with defective erythropoiesis and innate immune activation [PMID:40956846]. In neurons, VPS13A loss elevates DAG and dysregulates PKCβII signaling, impairing corticostriatal long-term depression and neuronal morphology [PMID:42237281]; truncating mutations that remove the PH domain underlie chorea-acanthocytosis [PMID:35950506].","teleology":[{"year":2018,"claim":"Established the core biochemical identity of VPS13A by showing its N-terminal domain forms a hydrophobic channel that directly transports glycerolipids, settling whether it is a lipid transporter rather than merely a tether.","evidence":"In vitro lipid transport reconstitution, structural analysis of the N-terminal domain, and co-localization imaging","pmids":["30093493"],"confidence":"High","gaps":["Did not resolve which contact sites are used in vivo under physiological demand","Lipid selectivity and directionality of transfer not defined"]},{"year":2019,"claim":"Defined how VPS13A is anchored to the ER and bridged to mitochondria and lipid droplets, identifying the adaptor logic underlying its contact-site localization.","evidence":"Reciprocal Co-IP mapping the FFAT-VAP-A interaction, C-terminal domain truncation for mitochondrial binding, live-cell imaging, and siRNA loss-of-function phenotyping","pmids":["30741634"],"confidence":"High","gaps":["Molecular identity of the mitochondrial C-terminal receptor not established here","Whether ER-mito tethering and lipid transfer are mechanistically separable left open"]},{"year":2015,"claim":"Connected VPS13A to autophagy across species, showing it is required for autophagosome formation and flux and that the C-terminal ATG2-homology region is the functional module.","evidence":"Dictyostelium TipC knockout with autophagy markers and flux assays, domain complementation, and confirmatory siRNA in HeLa cells","pmids":["25996471"],"confidence":"High","gaps":["Direct molecular mechanism linking lipid transfer to autophagosome biogenesis not defined","Relevant autophagy partner not yet identified at this stage"]},{"year":2019,"claim":"Placed VPS13A in endolysosomal trafficking by identifying RAB7A as a partner, expanding its role beyond ER-mitochondria contacts.","evidence":"Co-IP of VPS13A and RAB7A in HeLa and Dictyostelium plus endolysosomal marker analysis","pmids":["30709847"],"confidence":"Medium","gaps":["Interaction domain on VPS13A not mapped","Single lab; direct vs indirect RAB7A binding unresolved"]},{"year":2020,"claim":"Identified XK as a VPS13A partner that recruits it to specific contact sites, and linked the recruitment to disease mutations.","evidence":"Co-IP and overexpression relocalization assay in human cells with ChAc disease-mutant VPS13A","pmids":["32845802"],"confidence":"Medium","gaps":["Binding interface not yet mapped at this stage","Functional consequence of relocalization not measured"]},{"year":2022,"claim":"Resolved the molecular basis of XK recruitment, showing the VPS13A PH domain binds an XK cytosolic loop to form ER-PM contacts, and that this binding competes with other membrane-tethering interactions.","evidence":"Domain-level binding assays, AlphaFold modeling, competitive binding assays, and caudate neuron expression analysis","pmids":["35994651"],"confidence":"High","gaps":["Structural model not experimentally validated at this stage","Regulatory switch controlling competing localizations not fully defined"]},{"year":2022,"claim":"Demonstrated a physiological function for the VPS13A-XK complex, establishing it as essential for P2X7-driven phosphatidylserine scrambling and necrotic death in T cells.","evidence":"Genome-wide CRISPR screen, blue-native PAGE complex detection, phospholipid scrambling assays, and null-mutant cell lysis assays","pmids":["35140185"],"confidence":"High","gaps":["How lipid transfer mechanistically enables scrambling not resolved here","Generality beyond T cells not addressed"]},{"year":2022,"claim":"Mapped the PH domain as the XK-binding module and linked PH-domain-truncating patient mutations to loss of complex formation.","evidence":"Domain mutagenesis, Co-IP, co-localization imaging, and AlphaFold modeling","pmids":["35950506"],"confidence":"Medium","gaps":["Structural prediction not validated by experimental structure at this stage","Single lab"]},{"year":2022,"claim":"Showed VPS13A regulates lipid droplet abundance at ER-LD contacts under lipid loading, reinforcing its lipid-homeostatic role.","evidence":"CRISPR knockout in U-2 OS cells with lipid droplet quantification under oleate stimulation","pmids":["36147729"],"confidence":"Medium","gaps":["Directionality of lipid flux to/from droplets not determined","Single method, single lab"]},{"year":2023,"claim":"Identified SNX5 as the endosomal adaptor binding the VPS13A VAB domain, mapping a third recruitment mechanism and linking a conserved VAB residue to pathogenicity.","evidence":"Co-IP, domain truncation/mutation analysis, co-localization imaging, and yeast comparative genetics","pmids":["36977596"],"confidence":"Medium","gaps":["Functional consequence of SNX5-mediated endosomal localization not defined","Single lab"]},{"year":2023,"claim":"Provided a molecular link to autophagy machinery by showing VPS13A directly binds the scramblase ATG9A in a complex distinct from ATG9A-ATG2A.","evidence":"IP-mass spectrometry interactome with biochemical complex validation","pmids":["38294121"],"confidence":"Medium","gaps":["Functional role of the VPS13A-ATG9A complex in autophagy not established here","Binding interface not mapped"]},{"year":2023,"claim":"Showed that VPS13A-XK ER-PM contact formation requires a permissive cellular state, not merely XK presence, revealing state-dependent regulation of contact assembly.","evidence":"Overexpression co-localization imaging in K562 cells ± hemin differentiation with XK CRISPR KO and quantitative contact analysis","pmids":["38144430"],"confidence":"Medium","gaps":["The permissive factor or signal is not identified","Single lab, overexpression-based"]},{"year":2023,"claim":"Linked VPS13A loss to neuronal lipid signaling dysregulation, showing elevated DAG and PKCβII-dependent defects in corticostriatal plasticity and morphology.","evidence":"In vivo AAV knockdown, lipidomics, PKC isoform analysis, electrophysiology, behavior, and PKCβII pharmacological rescue","pmids":["42237281"],"confidence":"Medium","gaps":["Mechanistic link from impaired lipid transfer to DAG accumulation not fully defined","Single lab"]},{"year":2025,"claim":"Connected VPS13A-dependent autophagy to tissue pathology, showing autophagy impairment in skeletal muscle drives metabolic remodeling and accelerated aging that is reversible by rapamycin.","evidence":"Vps13a-/- mouse with autophagy flux assays, rapamycin rescue, patient muscle biopsies, and proteomics","pmids":["40275365"],"confidence":"Medium","gaps":["Whether muscle and neuronal phenotypes share one mechanism unresolved","Single lab"]},{"year":2025,"claim":"Established functional redundancy between VPS13A and VPS13C through genetic epistasis, showing combined loss causes embryonic lethality with defective erythropoiesis and innate immune activation.","evidence":"Vps13a/Vps13c double knockout mouse with embryonic phenotyping, erythroid assays, and innate immunity gene profiling","pmids":["40956846"],"confidence":"High","gaps":["The shared lipid species or membrane whose loss triggers innate immune activation not identified","Relative contribution of each paralog per tissue unresolved"]},{"year":2026,"claim":"Delivered the structural mechanism of the VPS13A-XKR1 complex, showing how PH-domain binding orients the lipid-transfer channel to deliver lipids to the cytosolic leaflet for scramblase-mediated equilibration.","evidence":"Near-atomic cryo-EM structure with molecular dynamics simulations (preprint)","pmids":["41542425"],"confidence":"High","gaps":["Structure with the physiological XK partner versus XKR1 paralog not directly compared","Preprint, not yet peer reviewed"]},{"year":2026,"claim":"Defined the VPS13A-XK binding interface at residue resolution and systematically classified patient variants by mechanism, separating expression defects from scramblase-activity defects and identifying a gain-of-function variant.","evidence":"Site-directed mutagenesis, phospholipid scrambling assays, expression analysis, and cell morphology in a mouse cell system","pmids":["41874565"],"confidence":"High","gaps":["In vivo consequences of variant classes not tested","Single lab"]},{"year":2026,"claim":"Confirmed in patient cells that VPS13A loss impairs lipid transfer into mitochondria and perturbs contact sites and mitochondrial calcium handling, validating the lipid-transfer model in a disease-relevant context.","evidence":"Labeled fatty acid transfer assay, mitochondrial calcium indicators, and super-resolution imaging in patient fibroblasts","pmids":["41552990"],"confidence":"Medium","gaps":["Causal link between lipid transfer defect and altered calcium uptake not mechanistically dissected","Single lab"]},{"year":null,"claim":"How VPS13A dynamically partitions among its competing adaptor-defined contact sites (ER-mitochondria, ER-PM, endosomes, lipid droplets) in response to cellular state, and which specific lipid flux underlies each disease-relevant phenotype, remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["The signal controlling competitive PH-domain partitioning is unknown","Tissue-specific lipid species transferred not identified","Mechanism linking lipid transfer to autophagy, neuronal DAG/PKC signaling, and calcium handling not unified"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0008289","term_label":"lipid binding","supporting_discovery_ids":[0,17,19]},{"term_id":"GO:0140104","term_label":"molecular carrier activity","supporting_discovery_ids":[0,17]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[1,5,8]}],"localization":[{"term_id":"GO:0005783","term_label":"endoplasmic reticulum","supporting_discovery_ids":[0,1,5]},{"term_id":"GO:0005739","term_label":"mitochondrion","supporting_discovery_ids":[1,19]},{"term_id":"GO:0005811","term_label":"lipid droplet","supporting_discovery_ids":[0,1,11]},{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[5,6,10]},{"term_id":"GO:0005768","term_label":"endosome","supporting_discovery_ids":[3,8]}],"pathway":[{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[0,11,19]},{"term_id":"R-HSA-9612973","term_label":"Autophagy","supporting_discovery_ids":[2,9,15]},{"term_id":"R-HSA-5357801","term_label":"Programmed Cell Death","supporting_discovery_ids":[6]},{"term_id":"R-HSA-5653656","term_label":"Vesicle-mediated transport","supporting_discovery_ids":[3]}],"complexes":["VPS13A-XK plasma membrane complex","VPS13A-ATG9A complex"],"partners":["XK","VAPA","SNX5","RAB7A","ATG9A","TBC1D1","XKR1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q96RL7","full_name":"Intermembrane lipid transfer protein VPS13A","aliases":["Chorea-acanthocytosis protein","Chorein","Vacuolar protein sorting-associated protein 13A"],"length_aa":3174,"mass_kda":360.3,"function":"Mediates the transfer of lipids between membranes at organelle contact sites (By similarity). Binds phospholipids (PubMed:34830155). Required for the formation or stabilization of ER-mitochondria contact sites which enable transfer of lipids between the ER and mitochondria (PubMed:30741634). Negatively regulates lipid droplet size and motility (PubMed:30741634). 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VPS13A binds to the ER and tethers it to mitochondria and lipid droplets, functioning as a lipid transporter at ER-organelle membrane contact sites.\",\n      \"method\": \"In vitro lipid transport reconstitution assay, structural analysis of N-terminal domain, subcellular fractionation and co-localization imaging\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro reconstitution of lipid transport, structural characterization, multiple orthogonal methods in a single rigorous study, widely replicated concept\",\n      \"pmids\": [\"30093493\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"VPS13A is a peripheral membrane protein localized at ER-mitochondria contact sites, lipid droplets, and the ER. It interacts with the ER-resident protein VAP-A via its FFAT domain, and its C-terminal domain mediates interaction with mitochondria. VPS13A depletion decreases ER-mitochondria contact sites, causes mitochondrial fragmentation, decreases mitophagy, and increases lipid droplet numbers.\",\n      \"method\": \"Co-immunoprecipitation (VAP-A interaction via FFAT domain), domain truncation mapping (C-terminal mitochondrial interaction), live-cell imaging, siRNA knockdown with quantitative phenotypic readouts\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP, domain mapping, live-cell imaging, multiple orthogonal methods with clean loss-of-function phenotypes\",\n      \"pmids\": [\"30741634\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"VPS13A (via its Dictyostelium ortholog TipC) is required for autophagy. TipC/VPS13A-null cells show a reduced number of autophagosomes and impaired autophagic flux. The C-terminal region containing the ATG2-homology domain and DUF1162 is sufficient to complement the mutant phenotype. Human VPS13A knockdown in HeLa cells also causes accumulation of autophagic markers and impaired autophagic flux.\",\n      \"method\": \"Genetic knockout in Dictyostelium, GFP-Atg18 and GFP-Atg8 autophagosome markers, proteolytic cleavage autophagic flux assay, domain complementation, siRNA knockdown in HeLa cells\",\n      \"journal\": \"Autophagy\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — clean KO with defined cellular phenotype, domain rescue, confirmed in two model systems (Dictyostelium and human cells)\",\n      \"pmids\": [\"25996471\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"VPS13A interacts with RAB7A (a key endosomal trafficking regulator) in both Dictyostelium and human HeLa cells. Loss of VPS13A impairs endocytic trafficking and lysosomal degradation, and disrupts membrane contact sites between mitochondria-endosomes and mitochondria-ER.\",\n      \"method\": \"Co-immunoprecipitation of VPS13A and RAB7A in HeLa cells, Dictyostelium genetic studies, endolysosomal marker analysis\",\n      \"journal\": \"Disease models & mechanisms\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — Co-IP interaction confirmed in two species, loss-of-function phenotype with lysosomal markers, single lab\",\n      \"pmids\": [\"30709847\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"XK forms a protein complex with VPS13A in human cells. Overexpressed XK relocalizes VPS13A from lipid droplets to subdomains of the ER. Two ChAc disease-linked missense mutations in VPS13A prevent this XK-induced relocalization, suggesting XK is a partner that recruits VPS13A to specific contact sites.\",\n      \"method\": \"Co-immunoprecipitation in human cells, overexpression relocalization assay, disease-mutant VPS13A analysis\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP, functional relocalization assay with disease mutations, single lab\",\n      \"pmids\": [\"32845802\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"VPS13A localizes at ER-plasma membrane (ER-PM) contact sites via binding of its PH domain to a cytosolic loop of the lipid scramblase XK. This interaction is regulated by an intramolecular interaction within XK. Binding of the VPS13A PH domain to XK is competitive with its binding to intracellular membranes mediating other tethering functions. Both VPS13A and XK are highly expressed in caudate neurons.\",\n      \"method\": \"Co-localization imaging, domain-level binding assays (PH domain), AlphaFold structural modeling, competitive binding assays, cell-type expression analysis\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — domain-level interaction mapping, structural modeling with functional validation, competitive binding assays, multiple orthogonal methods\",\n      \"pmids\": [\"35994651\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"In mouse T cells, VPS13A and XK form a complex at the plasma membrane (confirmed by blue-native PAGE) and are essential for P2X7 receptor-mediated phosphatidylserine exposure, phosphatidylcholine internalization, and necrotic cell death in response to extracellular ATP. Null mutation in either Xk or Vps13a blocks these processes.\",\n      \"method\": \"CRISPR/Cas9 genome-wide screen, blue-native PAGE (complex detection), phospholipid scrambling assays (annexin V/PtdSer exposure), cell lysis assay, T cell transformation system\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — CRISPR screen plus native PAGE complex confirmation, multiple functional readouts (PtdSer exposure, lipid internalization, cell lysis), clean null mutant phenotypes\",\n      \"pmids\": [\"35140185\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"The pleckstrin homology (PH) domain at the C-terminal region of VPS13A is required for complex formation with XK and for co-localization of VPS13A with XK within the cell. AlphaFold modeling predicted an interaction surface between VPS13A and XK; mutations at this interface disrupt both complex formation and co-localization. Disease-causing truncating mutations in VPS13A patients remove the PH domain.\",\n      \"method\": \"Domain mutagenesis, co-immunoprecipitation, co-localization imaging, AlphaFold structural modeling\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — domain mutagenesis plus Co-IP and localization, single lab, structural modeling not experimentally validated by crystallography\",\n      \"pmids\": [\"35950506\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"The sorting nexin SNX5 interacts with VPS13A and mediates its association with endosomal subdomains. This interaction involves the VPS13 adaptor-binding (VAB) domain of VPS13A and a PxP motif in SNX5. Mutation of a conserved asparagine in the VAB domain (also pathogenic in VPS13D) impairs this interaction. VPS13A C-terminal domain directs localization to mitochondria, while VAB-domain-containing fragments co-localize with SNX5 at endosomes.\",\n      \"method\": \"Co-immunoprecipitation, domain truncation/mutation analysis, co-localization imaging, yeast comparative genetics\",\n      \"journal\": \"Life science alliance\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP plus domain mapping with mutagenesis, single lab, supported by yeast comparative data\",\n      \"pmids\": [\"36977596\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"VPS13A directly interacts with ATG9A (the autophagy transmembrane lipid scramblase) and forms a complex distinct from the ATG9A-ATG2A complex, as revealed by mass spectrometry-based interactome analysis and validated biochemically.\",\n      \"method\": \"Immunoprecipitation mass spectrometry (interactome), biochemical complex validation\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — IP-MS interactome with biochemical validation of distinct complex, single lab\",\n      \"pmids\": [\"38294121\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"VPS13A interaction with XK at ER-PM contacts is cell-type/state dependent. In hemin-differentiated K562 erythroblast-like cells, tagged VPS13A robustly forms ER-PM contacts that require XK (abolished in XK KO cells). In undifferentiated K562 cells, despite similar XK levels, ER-PM contacts are rarely observed, indicating a permissive cellular state is required.\",\n      \"method\": \"Overexpression co-localization imaging in K562 cells ± hemin differentiation, XK CRISPR KO, quantitative contact site analysis\",\n      \"journal\": \"Contact (Thousand Oaks (Ventura County, Calif.))\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean KO with quantitative imaging phenotype, two cell states compared, single lab\",\n      \"pmids\": [\"38144430\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Loss of VPS13A (or VPS13C) in U-2 OS cells results in reduced lipid droplet abundance under oleate-stimulated conditions, implicating VPS13A in lipid droplet regulation at ER-lipid droplet contact sites.\",\n      \"method\": \"CRISPR-Cas9 knockout (exon 2 deletion/frameshift), lipid droplet quantification under oleate stimulation\",\n      \"journal\": \"Contact (Thousand Oaks (Ventura County, Calif.))\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean CRISPR KO with defined phenotypic readout, single lab, single method\",\n      \"pmids\": [\"36147729\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"In differentiated PC12 cells, VPS13A (chorein) localizes to dense-core vesicles (DCVs) containing dopamine and co-localizes with synaptotagmin I at neurite termini. Stable expression of the C-terminal fragment of chorein increases K+-induced dopamine release, suggesting VPS13A is involved in exocytosis of DCVs.\",\n      \"method\": \"Immunocytochemistry, sucrose density gradient fractionation, dopamine release assay (K+-stimulated exocytosis), stable overexpression\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, partial mechanistic follow-up, C-terminal fragment overexpression effect without full loss-of-function validation\",\n      \"pmids\": [\"22366033\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"VPS13A and VPS13C interact with TBC1D1 (a Rab-GTPase activating protein) in C2C12 myotubes via TBC1D1's phosphotyrosine binding (PTB) domains. Depletion of VPS13A causes a post-transcriptional increase in cellular GLUT4 protein and enhanced cell-surface GLUT4 upon AMPK activation, specifically affecting GLUT4 homeostasis.\",\n      \"method\": \"Quantitative proteomics (unbiased Co-IP-MS), domain mapping, siRNA depletion, GLUT4 cell-surface assay (AMPK-stimulated)\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — unbiased MS interactome plus functional depletion phenotype with specific GLUT4 readout, single lab\",\n      \"pmids\": [\"33087848\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"VPS13A (chorein) promotes PI3K activation and supports cell survival signaling: siRNA silencing in rhabdomyosarcoma cells reduces phosphorylated PI3K, downregulates BCL-2, upregulates BAX, causes mitochondrial depolarization, caspase-3 activation, and apoptosis.\",\n      \"method\": \"siRNA silencing, Western blot (phospho-PI3K, BCL-2, BAX), FACS apoptosis analysis, mitochondrial membrane potential assay\",\n      \"journal\": \"Oncotarget\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, single depletion approach, cancer cell line context with no pathway placement beyond correlation\",\n      \"pmids\": [\"25871399\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Absence of VPS13A impairs autophagy in skeletal muscle, leading to pathologic metabolic remodeling, increased protein/lipid oxidation, defects in myofibril stability, and accumulation of the senescence marker NCAM1 in Vps13a-/- mice. Rapamycin treatment rescued accumulation of LAMP1, p62, and NCAM1, linking impaired autophagy to accelerated aging in the absence of VPS13A.\",\n      \"method\": \"Vps13a-/- mouse model, starvation/colchicine autophagy assay, rapamycin rescue, patient muscle biopsies, proteomics, immunohistochemistry\",\n      \"journal\": \"Acta neuropathologica communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — mouse KO plus human biopsy validation, rapamycin rescue provides mechanistic link, multiple readouts, single lab\",\n      \"pmids\": [\"40275365\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"VPS13A knockdown in cortical neurons and striatum of mice increases DAG species, reduces PKCβII concentration while increasing PKCα/βII phosphorylation, and causes increased neuronal branching, decreased BDNF and PSD-95, impaired corticostriatal long-term depression (LTD), and hyperlocomotion. Pharmacological inhibition of PKCβII rescues aberrant neuronal morphology and spine density loss.\",\n      \"method\": \"Lipidomics (DAG quantification), Western blot (PKC isoforms and phosphorylation), AAV-mediated VPS13A knockdown in vivo, electrophysiology (LTD), behavioral assays, pharmacological rescue (PKCβII inhibitor)\",\n      \"journal\": \"BMC biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo KD with lipidomics plus electrophysiology and pharmacological rescue, single lab, multiple orthogonal methods\",\n      \"pmids\": [\"42237281\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"Cryo-EM structure of VPS13A complexed with the scramblase XKR1 at near-atomic resolution shows that VPS13A interacts with XKR1 via its PH domain, orienting VPS13A's lipid-transfer domain to deliver lipids to the cytosolic leaflet of the acceptor membrane. Molecular dynamics simulations confirm robust lipid transfer in this configuration, with scramblase activity allowing equilibration of newly transferred lipids between membrane leaflets.\",\n      \"method\": \"Cryo-electron microscopy (near-atomic resolution), molecular dynamics simulations\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — cryo-EM structure plus MD simulations in a single study; preprint but provides direct structural mechanism\",\n      \"pmids\": [\"41542425\"],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"Mutational analysis of the VPS13A-XK interaction interface revealed that VPS13A binds XK through a C-terminal β-strand that interacts with a β-hairpin in the central region of XK, and this interaction is essential for scramblase activity. Ten patient-derived VPS13A variants were classified into four functional groups: (a) reduced expression (L67P, I90K, W2453R); (b) normal expression but absent scramblase activity (A1091P, M3080R); (c) modest impairment of expression or activity; and (d) a gain-of-function variant (I2763R) that alters cell size and disrupts ER independently of XK. XKR2, a XK paralog with a similar β-hairpin, also associates with VPS13A and supports phospholipid scrambling.\",\n      \"method\": \"Site-directed mutagenesis, phospholipid scrambling functional assay, Western blot (expression), cell morphology analysis, mouse cell expression system\",\n      \"journal\": \"The Journal of clinical investigation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — reconstitution plus mutagenesis with functional assay, systematic characterization of disease mutations, single lab but multiple orthogonal methods\",\n      \"pmids\": [\"41874565\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"Loss of VPS13A in patient-derived fibroblasts causes impaired lipid transfer into mitochondria, reduced lipid droplet formation, disturbance of membrane contact sites, and unusual mitochondrial calcium uptake behavior, as demonstrated by labeled fatty acid tracking and mitochondrial calcium indicator assays.\",\n      \"method\": \"Labeled fatty acid transfer assay, mitochondrial calcium indicator (Rhod-2 AM), super-resolution microscopy (Airyscan2), VPS13A-deficient patient fibroblasts vs. healthy controls\",\n      \"journal\": \"Movement disorders\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — patient fibroblasts with labeled lipid tracking and calcium assays plus super-resolution imaging, single lab\",\n      \"pmids\": [\"41552990\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"VPS13A and VPS13C have partially redundant lipid transfer functions: single Vps13a or Vps13c KO mice are viable, but double KO (DKO) mice die at midgestation with defective erythropoiesis, innate immune activation (upregulation of ISGs, RIG-I, MDA5), suggesting that combined loss of lipid flux from both proteins causes loss of organelle membrane integrity.\",\n      \"method\": \"Vps13a/Vps13c double knockout mouse, embryonic phenotyping, erythroid differentiation assays, innate immunity gene expression profiling\",\n      \"journal\": \"PLoS biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic epistasis via double KO with clear embryonic lethal phenotype and molecular readouts, published peer-reviewed and replicated in preprint\",\n      \"pmids\": [\"40956846\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"ATG9A lipid scramblase activity and VPS13A lipid transfer protein activity are both required for efficient plasma membrane repair in mammalian cells.\",\n      \"method\": \"Plasma membrane damage assay, genetic knockdown/KO of ATG9A and VPS13A, functional complementation\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean KO/KD with defined functional readout (membrane repair), single lab, ATG9A-VPS13A functional epistasis\",\n      \"pmids\": [\"42044337\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"VPS13A (chorein) is a bridge-like bulk lipid transfer protein that localizes at multiple ER-organelle membrane contact sites (ER-mitochondria, ER-lipid droplets, ER-endosomes, ER-plasma membrane), where it transports glycerolipids through a hydrophobic tubular channel formed by its N-terminal domain; it is recruited to specific contact sites via adaptor interactions—including binding of its FFAT domain to VAP-A (ER), its C-terminal domain to mitochondria, its VAB domain to SNX5 (endosomes), and its PH domain to the lipid scramblase XK (plasma membrane)—and the VPS13A-XK complex is essential for P2X7-stimulated phosphatidylserine scrambling and necrotic cell death in T cells, with loss of VPS13A impairing ER-mitochondria contacts, mitochondrial morphology, lipid droplet homeostasis, lysosomal degradation, autophagy, and DAG/PKC-mediated neuronal signaling.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"VPS13A (chorein) is a bridge-like bulk lipid transfer protein that moves glycerolipids between organelle membranes at ER-organelle contact sites, with its N-terminal domain forming a hydrophobic tubular channel that solubilizes and shuttles lipids in vitro [#0]. It is recruited to distinct contact sites through modular adaptor interactions: an FFAT-mediated interaction with the ER protein VAP-A and a C-terminal domain that engages mitochondria [#1], a VAB domain that binds a PxP motif in SNX5 at endosomal subdomains [#8], and a C-terminal PH domain that binds a cytosolic loop of the plasma-membrane lipid scramblase XK in a manner competitive with its other membrane-tethering activities [#5]. The VPS13A-XK complex pairs lipid transfer with scramblase activity to deliver and equilibrate lipids across membrane leaflets [#17], and this complex is essential for P2X7-stimulated phosphatidylserine exposure and necrotic cell death in T cells [#6]; the C-terminal β-strand of VPS13A docks into a β-hairpin of XK, an interface required for scramblase function and disrupted by patient-derived variants [#18]. Through these contacts VPS13A maintains ER-mitochondria tethering, mitochondrial morphology and lipid import, and lipid droplet homeostasis, and its loss fragments mitochondria and perturbs lipid droplet abundance [#1, #11, #19]. VPS13A also supports autophagy and autophagic flux—acting in part through a direct interaction with the lipid scramblase ATG9A [#2, #9]—and contributes to endolysosomal trafficking via RAB7A [#3] and to plasma membrane repair together with ATG9A [#21]. VPS13A and the paralog VPS13C are partially redundant, since combined loss is embryonic lethal with defective erythropoiesis and innate immune activation [#20]. In neurons, VPS13A loss elevates DAG and dysregulates PKCβII signaling, impairing corticostriatal long-term depression and neuronal morphology [#16]; truncating mutations that remove the PH domain underlie chorea-acanthocytosis [#7].\",\n  \"teleology\": [\n    {\n      \"year\": 2018,\n      \"claim\": \"Established the core biochemical identity of VPS13A by showing its N-terminal domain forms a hydrophobic channel that directly transports glycerolipids, settling whether it is a lipid transporter rather than merely a tether.\",\n      \"evidence\": \"In vitro lipid transport reconstitution, structural analysis of the N-terminal domain, and co-localization imaging\",\n      \"pmids\": [\"30093493\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not resolve which contact sites are used in vivo under physiological demand\", \"Lipid selectivity and directionality of transfer not defined\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Defined how VPS13A is anchored to the ER and bridged to mitochondria and lipid droplets, identifying the adaptor logic underlying its contact-site localization.\",\n      \"evidence\": \"Reciprocal Co-IP mapping the FFAT-VAP-A interaction, C-terminal domain truncation for mitochondrial binding, live-cell imaging, and siRNA loss-of-function phenotyping\",\n      \"pmids\": [\"30741634\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular identity of the mitochondrial C-terminal receptor not established here\", \"Whether ER-mito tethering and lipid transfer are mechanistically separable left open\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Connected VPS13A to autophagy across species, showing it is required for autophagosome formation and flux and that the C-terminal ATG2-homology region is the functional module.\",\n      \"evidence\": \"Dictyostelium TipC knockout with autophagy markers and flux assays, domain complementation, and confirmatory siRNA in HeLa cells\",\n      \"pmids\": [\"25996471\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct molecular mechanism linking lipid transfer to autophagosome biogenesis not defined\", \"Relevant autophagy partner not yet identified at this stage\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Placed VPS13A in endolysosomal trafficking by identifying RAB7A as a partner, expanding its role beyond ER-mitochondria contacts.\",\n      \"evidence\": \"Co-IP of VPS13A and RAB7A in HeLa and Dictyostelium plus endolysosomal marker analysis\",\n      \"pmids\": [\"30709847\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Interaction domain on VPS13A not mapped\", \"Single lab; direct vs indirect RAB7A binding unresolved\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Identified XK as a VPS13A partner that recruits it to specific contact sites, and linked the recruitment to disease mutations.\",\n      \"evidence\": \"Co-IP and overexpression relocalization assay in human cells with ChAc disease-mutant VPS13A\",\n      \"pmids\": [\"32845802\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Binding interface not yet mapped at this stage\", \"Functional consequence of relocalization not measured\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Resolved the molecular basis of XK recruitment, showing the VPS13A PH domain binds an XK cytosolic loop to form ER-PM contacts, and that this binding competes with other membrane-tethering interactions.\",\n      \"evidence\": \"Domain-level binding assays, AlphaFold modeling, competitive binding assays, and caudate neuron expression analysis\",\n      \"pmids\": [\"35994651\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural model not experimentally validated at this stage\", \"Regulatory switch controlling competing localizations not fully defined\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Demonstrated a physiological function for the VPS13A-XK complex, establishing it as essential for P2X7-driven phosphatidylserine scrambling and necrotic death in T cells.\",\n      \"evidence\": \"Genome-wide CRISPR screen, blue-native PAGE complex detection, phospholipid scrambling assays, and null-mutant cell lysis assays\",\n      \"pmids\": [\"35140185\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How lipid transfer mechanistically enables scrambling not resolved here\", \"Generality beyond T cells not addressed\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Mapped the PH domain as the XK-binding module and linked PH-domain-truncating patient mutations to loss of complex formation.\",\n      \"evidence\": \"Domain mutagenesis, Co-IP, co-localization imaging, and AlphaFold modeling\",\n      \"pmids\": [\"35950506\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Structural prediction not validated by experimental structure at this stage\", \"Single lab\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Showed VPS13A regulates lipid droplet abundance at ER-LD contacts under lipid loading, reinforcing its lipid-homeostatic role.\",\n      \"evidence\": \"CRISPR knockout in U-2 OS cells with lipid droplet quantification under oleate stimulation\",\n      \"pmids\": [\"36147729\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Directionality of lipid flux to/from droplets not determined\", \"Single method, single lab\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Identified SNX5 as the endosomal adaptor binding the VPS13A VAB domain, mapping a third recruitment mechanism and linking a conserved VAB residue to pathogenicity.\",\n      \"evidence\": \"Co-IP, domain truncation/mutation analysis, co-localization imaging, and yeast comparative genetics\",\n      \"pmids\": [\"36977596\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional consequence of SNX5-mediated endosomal localization not defined\", \"Single lab\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Provided a molecular link to autophagy machinery by showing VPS13A directly binds the scramblase ATG9A in a complex distinct from ATG9A-ATG2A.\",\n      \"evidence\": \"IP-mass spectrometry interactome with biochemical complex validation\",\n      \"pmids\": [\"38294121\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional role of the VPS13A-ATG9A complex in autophagy not established here\", \"Binding interface not mapped\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Showed that VPS13A-XK ER-PM contact formation requires a permissive cellular state, not merely XK presence, revealing state-dependent regulation of contact assembly.\",\n      \"evidence\": \"Overexpression co-localization imaging in K562 cells ± hemin differentiation with XK CRISPR KO and quantitative contact analysis\",\n      \"pmids\": [\"38144430\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"The permissive factor or signal is not identified\", \"Single lab, overexpression-based\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Linked VPS13A loss to neuronal lipid signaling dysregulation, showing elevated DAG and PKCβII-dependent defects in corticostriatal plasticity and morphology.\",\n      \"evidence\": \"In vivo AAV knockdown, lipidomics, PKC isoform analysis, electrophysiology, behavior, and PKCβII pharmacological rescue\",\n      \"pmids\": [\"42237281\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanistic link from impaired lipid transfer to DAG accumulation not fully defined\", \"Single lab\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Connected VPS13A-dependent autophagy to tissue pathology, showing autophagy impairment in skeletal muscle drives metabolic remodeling and accelerated aging that is reversible by rapamycin.\",\n      \"evidence\": \"Vps13a-/- mouse with autophagy flux assays, rapamycin rescue, patient muscle biopsies, and proteomics\",\n      \"pmids\": [\"40275365\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether muscle and neuronal phenotypes share one mechanism unresolved\", \"Single lab\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Established functional redundancy between VPS13A and VPS13C through genetic epistasis, showing combined loss causes embryonic lethality with defective erythropoiesis and innate immune activation.\",\n      \"evidence\": \"Vps13a/Vps13c double knockout mouse with embryonic phenotyping, erythroid assays, and innate immunity gene profiling\",\n      \"pmids\": [\"40956846\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"The shared lipid species or membrane whose loss triggers innate immune activation not identified\", \"Relative contribution of each paralog per tissue unresolved\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Delivered the structural mechanism of the VPS13A-XKR1 complex, showing how PH-domain binding orients the lipid-transfer channel to deliver lipids to the cytosolic leaflet for scramblase-mediated equilibration.\",\n      \"evidence\": \"Near-atomic cryo-EM structure with molecular dynamics simulations (preprint)\",\n      \"pmids\": [\"41542425\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structure with the physiological XK partner versus XKR1 paralog not directly compared\", \"Preprint, not yet peer reviewed\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Defined the VPS13A-XK binding interface at residue resolution and systematically classified patient variants by mechanism, separating expression defects from scramblase-activity defects and identifying a gain-of-function variant.\",\n      \"evidence\": \"Site-directed mutagenesis, phospholipid scrambling assays, expression analysis, and cell morphology in a mouse cell system\",\n      \"pmids\": [\"41874565\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"In vivo consequences of variant classes not tested\", \"Single lab\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Confirmed in patient cells that VPS13A loss impairs lipid transfer into mitochondria and perturbs contact sites and mitochondrial calcium handling, validating the lipid-transfer model in a disease-relevant context.\",\n      \"evidence\": \"Labeled fatty acid transfer assay, mitochondrial calcium indicators, and super-resolution imaging in patient fibroblasts\",\n      \"pmids\": [\"41552990\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Causal link between lipid transfer defect and altered calcium uptake not mechanistically dissected\", \"Single lab\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How VPS13A dynamically partitions among its competing adaptor-defined contact sites (ER-mitochondria, ER-PM, endosomes, lipid droplets) in response to cellular state, and which specific lipid flux underlies each disease-relevant phenotype, remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"The signal controlling competitive PH-domain partitioning is unknown\", \"Tissue-specific lipid species transferred not identified\", \"Mechanism linking lipid transfer to autophagy, neuronal DAG/PKC signaling, and calcium handling not unified\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0008289\", \"supporting_discovery_ids\": [0, 17, 19]},\n      {\"term_id\": \"GO:0140104\", \"supporting_discovery_ids\": [0, 17]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [1, 5, 8]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005783\", \"supporting_discovery_ids\": [0, 1, 5]},\n      {\"term_id\": \"GO:0005739\", \"supporting_discovery_ids\": [1, 19]},\n      {\"term_id\": \"GO:0005811\", \"supporting_discovery_ids\": [0, 1, 11]},\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [5, 6, 10]},\n      {\"term_id\": \"GO:0005768\", \"supporting_discovery_ids\": [3, 8]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [0, 11, 19]},\n      {\"term_id\": \"R-HSA-9612973\", \"supporting_discovery_ids\": [2, 9, 15]},\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [6]},\n      {\"term_id\": \"R-HSA-5653656\", \"supporting_discovery_ids\": [3]}\n    ],\n    \"complexes\": [\n      \"VPS13A-XK plasma membrane complex\",\n      \"VPS13A-ATG9A complex\"\n    ],\n    \"partners\": [\n      \"XK\",\n      \"VAPA\",\n      \"SNX5\",\n      \"RAB7A\",\n      \"ATG9A\",\n      \"TBC1D1\",\n      \"XKR1\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":7,"faith_pct":100.0}}