{"gene":"VPS13C","run_date":"2026-06-11T09:02:06","timeline":{"discoveries":[{"year":2018,"finding":"The N-terminal portion of VPS13C forms a tubular structure with a hydrophobic cavity capable of solubilizing and transporting glycerolipids between membranes in vitro. VPS13C binds to the ER and tethers it to late endosomes/lysosomes and lipid droplets, identifying it as a lipid transporter at ER-organelle contact sites.","method":"In vitro lipid transport reconstitution assay; Co-fractionation and co-localization by fluorescence microscopy; structural analysis of N-terminal domain","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro lipid transport reconstitution combined with structural analysis and localization experiments, replicated across multiple organelle contacts","pmids":["30093493"],"is_preprint":false},{"year":2016,"finding":"VPS13C partly localizes to the outer membrane of mitochondria. Silencing of VPS13C causes lower mitochondrial membrane potential, mitochondrial fragmentation, increased respiration rates, and exacerbated PINK1/Parkin-dependent mitophagy, placing VPS13C upstream of this mitophagy pathway.","method":"siRNA-mediated knockdown in cell models; mitochondrial membrane potential assay; respiration measurements; fluorescence microscopy for mitochondrial morphology; PINK1/Parkin mitophagy pathway readouts","journal":"American journal of human genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — clean KD with multiple defined cellular phenotypes in a single lab; mitochondrial localization and pathway position established but not independently replicated at structural level","pmids":["26942284"],"is_preprint":false},{"year":2022,"finding":"VPS13C depletion in HeLa cells causes accumulation of lysosomes with altered lipid profiles, including accumulation of di-22:6-BMP. Loss of VPS13C activates the cGAS-STING innate immune pathway through elevated cytosolic mitochondrial DNA combined with impaired lysosome-dependent degradation of activated STING.","method":"siRNA knockdown in HeLa cells; lipidomic profiling; cGAS-STING pathway activation assays; measurement of cytosolic mtDNA; STING degradation assays","journal":"The Journal of cell biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods (lipidomics, pathway assays, mtDNA measurement) in single lab","pmids":["35657605"],"is_preprint":false},{"year":2022,"finding":"Cryo-electron tomography of HeLa cells overexpressing VPS13C in situ, combined with AlphaFold-based full-length structural modeling, reveals that VPS13C adopts an ~30-nm rod with a continuous hydrophobic groove spanning its length. Rod-like densities bridging ER and endo/lysosome membranes were observed in situ, providing direct structural evidence for a bridge-like lipid transport mechanism.","method":"AlphaFold structural prediction; cryo-focused ion beam (cryo-FIB) milling; cryo-electron tomography (cryo-ET) in situ in HeLa cells overexpressing full-length or internally truncated VPS13C with VAP","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1 / Strong — cryo-ET in situ structural evidence combined with genetic truncation controls and full-length modeling, multiple orthogonal structural approaches","pmids":["35858323"],"is_preprint":false},{"year":2016,"finding":"VPS13C is identified as a major binding partner of galectin-12. VPS13C is required for galectin-12 protein stability; knockdown of Vps13c markedly reduces galectin-12 steady-state levels by promoting its degradation through the lysosomal pathway, and impairs adipocyte differentiation.","method":"Co-immunoprecipitation/pulldown to identify VPS13C as galectin-12-binding protein; siRNA knockdown; lysosomal degradation assays; adipocyte differentiation assays","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP binding identification plus functional KD with defined phenotype (galectin-12 stability, adipogenesis), single lab","pmids":["27073999"],"is_preprint":false},{"year":2020,"finding":"VPS13C interacts with TBC1D1 via its phosphotyrosine binding (PTB) domains in C2C12 myotubes. Depletion of VPS13C causes a post-transcriptional increase in cellular GLUT4 protein and enhanced cell surface GLUT4 levels in response to AMPK activation, specifically affecting GLUT4 homeostasis.","method":"Unbiased quantitative proteomics (mass spectrometry) to identify TBC1D1-interacting proteins; siRNA depletion; cell surface GLUT4 assay; western blotting","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — MS-based interaction identification plus KD with specific phenotypic readout (GLUT4 levels/trafficking), single lab","pmids":["33087848"],"is_preprint":false},{"year":2021,"finding":"Compound heterozygous missense mutations p.Trp395Cys and p.Ala444Pro in VPS13C abolish its endosomal/lysosomal localization when overexpressed in HeLa or SH-SY5Y cells, demonstrating that these residues are required for proper subcellular targeting.","method":"Overexpression of wild-type or mutant VPS13C in HeLa and SH-SY5Y cells; fluorescence microscopy to assess endosomal/lysosomal localization","journal":"Acta neuropathologica communications","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — localization assay with functional mutagenesis in two cell lines, single lab","pmids":["33579389"],"is_preprint":false},{"year":2022,"finding":"Loss of VPS13A or VPS13C in U-2 OS cells via CRISPR-Cas9 knockout results in reduced lipid droplet abundance under oleate-stimulated conditions, implicating both proteins in lipid droplet regulation at ER-lipid droplet contact sites.","method":"CRISPR-Cas9 knockout of VPS13A and VPS13C (exon 2 deletion); lipid droplet quantification under oleate stimulation","journal":"Contact (Thousand Oaks)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — clean CRISPR KO with defined phenotypic readout, single lab, single method","pmids":["36147729"],"is_preprint":false},{"year":2024,"finding":"In human iPSC-derived dopaminergic neurons, loss of VPS13C disrupts lysosomal morphology and dynamics with increased inter-lysosomal contacts, impaired lysosomal motility and distribution, and defective lysosomal hydrolytic activity and acidification. Rab10 was identified as a phospho-dependent interactor of VPS13C on lysosomes; loss of VPS13C decreased phospho-Rab10-mediated lysosomal stress response.","method":"Live-cell microscopy in iPSC-derived dopaminergic neurons with VPS13C loss-of-function; lysosomal functional assays (hydrolytic activity, acidification); co-immunoprecipitation/interaction assays to identify phospho-Rab10 as VPS13C interactor","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — disease-relevant human neuronal model, multiple orthogonal functional readouts (morphology, motility, hydrolysis, acidification), plus binding partner identification, single lab with comprehensive approach","pmids":["38358348"],"is_preprint":false},{"year":2025,"finding":"Following lysosome membrane perturbation, VPS13C rapidly relocates from the cytosol to the lysosome surface where it tethers lysosome membranes to the ER. This recruitment depends on Rab7 and requires a signal at the damaged lysosome surface that releases an autoinhibited state of VPS13C, where the VAB domain is blocked from accessing lysosome-bound Rab7. LRRK2 is recruited to damaged lysosomes at much later stages and by different mechanisms.","method":"Live-cell fluorescence microscopy following lysosome damage induction; genetic approaches to demonstrate Rab7 dependence; functional analysis of VAB domain accessibility; comparison with LRRK2 recruitment kinetics","journal":"Nature cell biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — live imaging with multiple genetic and pharmacological perturbations, mechanistic dissection of VAB domain autoinhibition, published in peer-reviewed journal","pmids":["40211074"],"is_preprint":false},{"year":2025,"finding":"Cryo-EM structure of intact VPS13C at near-atomic resolution reveals a lipid-transfer-nonpermissive conformation where the built-in C-terminal VAB adaptor module blocks the end of the lipid transfer bridge, interfering with lipid delivery. Calmodulin was identified as a VPS13C binding partner, suggesting calcium-dependent regulation of VPS13C lipid transfer activity.","method":"Cryo-EM structure determination of full-length VPS13C; co-purification to identify calmodulin as binding partner","journal":"bioRxiv","confidence":"High","confidence_rationale":"Tier 1 / Moderate — near-atomic cryo-EM structure of intact protein with mechanistic interpretation of autoinhibitory conformation; single lab preprint","pmids":["41292763"],"is_preprint":true},{"year":2025,"finding":"VPS13C promotes ER-Salmonella-containing vacuole (SCV) contact formation, controls SCV positioning in host cells, regulates SCV morphology and fission, and facilitates cell-to-cell spread of S. Typhimurium, establishing VPS13C as a regulator of intracellular bacterial vacuole dynamics.","method":"BioID proximity labeling proteomics of SCV surface; functional knockdown/knockout studies of VPS13C with SCV morphology, fission, positioning, and bacterial spread readouts","journal":"PLoS pathogens","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — BioID identification plus functional studies with multiple cellular phenotype readouts, single lab","pmids":["40953080"],"is_preprint":false},{"year":2025,"finding":"VPS13C's ATG2C domain acts as a sensor of damage-induced lipid packing defects at lysosomes, triggering a conformational change in the C-terminus upon lysosomal membrane damage. ER-lysosome contacts formed by VPS13C provide binding platforms for OSBP/ORPs to enable ER wrapping of damaged lysosomes. VPS13C is essential for large-scale ER-to-lysosome lipid delivery required for lysosomal repair.","method":"Unbiased proteomics; conformational change analysis; directional lipid transport chemical assay; OSBP/ORP co-localization and functional studies; lysosome damage and repair assays","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods in single lab preprint; mechanistic dissection of ATG2C domain sensing and lipid transfer directionality","pmids":["bio_10.1101_2025.10.23.684214"],"is_preprint":true},{"year":2025,"finding":"Vps13a/Vps13c double knockout (DKO) mice die at midgestation with defective embryonic erythropoiesis and innate immune activation (upregulation of ISGs, RIG-I, and MDA5), while single knockouts are viable. This genetic epistasis demonstrates partially redundant lipid transport functions between VPS13A and VPS13C despite their distinct subcellular localizations.","method":"CRISPR/genetic double knockout mouse model; embryonic lethality assessment; erythroid differentiation assays; innate immunity gene expression analysis","journal":"PLoS biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — clean double-KO mouse genetic epistasis with multiple mechanistic readouts (erythropoiesis, innate immunity activation), peer-reviewed publication","pmids":["40956846"],"is_preprint":false},{"year":2016,"finding":"Beta-cell-specific deletion of Vps13c in mice results in significantly increased glucose-stimulated intracellular free Ca2+ in islets from female knockout mice, suggesting impaired Ca2+ sensitivity of the insulin secretory machinery, though glucose-stimulated insulin secretion was not altered in vitro.","method":"Conditional knockout mice (floxed Vps13c x Ins1-Cre); OGTT; intracellular Ca2+ imaging in isolated islets; glucose-stimulated insulin secretion assay","journal":"American journal of physiology. Endocrinology and metabolism","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — clean conditional KO with Ca2+ imaging phenotype, but effect was sex-specific and modest; single lab","pmids":["27329800"],"is_preprint":false}],"current_model":"VPS13C is a bridge-like lipid transfer protein that localizes at ER contact sites with late endosomes/lysosomes and lipid droplets, where it transports bulk glycerolipids between adjacent membranes through a continuous hydrophobic groove spanning its ~30-nm rod-like structure; upon lysosome damage, VPS13C is recruited from the cytosol to damaged lysosomes in a Rab7-dependent manner by releasing a VAB-domain-mediated autoinhibited conformation, facilitating ER-lysosome tethering, large-scale lipid delivery for lysosomal repair, and recruitment of OSBP/ORP proteins, while loss of VPS13C causes lysosomal dysfunction, altered lipid profiles, cGAS-STING innate immune activation via cytosolic mtDNA, and exacerbated PINK1/Parkin-dependent mitophagy, collectively linking its lipid transport function to Parkinson's disease pathogenesis."},"narrative":{"mechanistic_narrative":"VPS13C is a bridge-like lipid transfer protein that operates at endoplasmic reticulum membrane contact sites, where it physically tethers the ER to late endosomes/lysosomes and lipid droplets and conveys bulk glycerolipids between the apposed bilayers [PMID:30093493]. Structural work shows the protein folds into an ~30-nm rod traversed by a continuous hydrophobic groove, with rod-like densities seen bridging ER and endo/lysosome membranes in situ, providing a direct physical basis for membrane-to-membrane lipid transfer [PMID:35858323]. The lipid-transfer reaction is conformationally gated: the C-terminal VAB adaptor module folds back to block the end of the transfer bridge in an autoinhibited, transfer-nonpermissive state [PMID:41292763], and following lysosome membrane damage VPS13C is rapidly recruited from the cytosol to the lysosome surface in a Rab7-dependent manner that relieves this autoinhibition and establishes ER-lysosome contacts for large-scale lipid delivery and lysosomal repair [PMID:40211074]. Loss of VPS13C produces lysosomes with altered lipid profiles and defective hydrolytic activity, motility, and acidification, and triggers cGAS-STING innate immune activation through elevated cytosolic mitochondrial DNA and impaired STING degradation [PMID:35657605, PMID:38358348]. VPS13C also localizes partly to mitochondria and acts upstream of PINK1/Parkin-dependent mitophagy [PMID:26942284], and partially redundant lipid-transport functions with VPS13A are essential for embryonic erythropoiesis, as Vps13a/Vps13c double-knockout mice die at midgestation with innate immune activation [PMID:40956846]. Compound heterozygous missense mutations that abolish endolysosomal targeting link these functions to disease [PMID:33579389]. The protein engages additional partners and contexts—Rab10 and phospho-Rab10 lysosomal stress signaling [PMID:38358348], OSBP/ORP recruitment for ER wrapping of damaged lysosomes [PMID:bio_10.1101_2025.10.23.684214], TBC1D1/GLUT4 homeostasis [PMID:33087848], galectin-12 stability and adipogenesis [PMID:27073999], and ER-Salmonella vacuole dynamics [PMID:40953080].","teleology":[{"year":2016,"claim":"Established a mitochondrial connection by placing VPS13C upstream of a defined quality-control pathway, providing the first functional handle on its cellular role.","evidence":"siRNA knockdown with membrane potential, respiration, morphology, and PINK1/Parkin mitophagy readouts in cell models","pmids":["26942284"],"confidence":"Medium","gaps":["Does not establish direct molecular activity at mitochondria","Mitochondrial localization not confirmed at structural level"]},{"year":2016,"claim":"Identified the first direct binding partner (galectin-12) and a role in protein stability and adipocyte differentiation, broadening VPS13C beyond mitochondria.","evidence":"Co-IP/pulldown to identify galectin-12 binding, plus siRNA knockdown and lysosomal degradation/adipogenesis assays","pmids":["27073999"],"confidence":"Medium","gaps":["Mechanism linking VPS13C to galectin-12 degradation unresolved","Relationship to lipid transfer function unclear"]},{"year":2018,"claim":"Defined the core molecular activity—solubilization and transfer of glycerolipids between membranes—and identified VPS13C as a tether at ER-organelle contact sites.","evidence":"In vitro lipid transport reconstitution, co-fractionation/co-localization microscopy, and N-terminal structural analysis","pmids":["30093493"],"confidence":"High","gaps":["Full-length architecture not resolved","Directionality and regulation of transfer not addressed"]},{"year":2022,"claim":"Connected VPS13C loss to lysosomal lipid abnormalities and to cGAS-STING innate immune activation, linking lipid transport to immune signaling.","evidence":"siRNA knockdown in HeLa with lipidomics, cytosolic mtDNA measurement, and cGAS-STING/STING degradation assays","pmids":["35657605"],"confidence":"Medium","gaps":["Causal chain from lipid defect to mtDNA release not fully dissected","Single cell line"]},{"year":2022,"claim":"Provided direct in situ structural evidence that VPS13C is a ~30-nm rod with a continuous hydrophobic groove physically bridging ER and endo/lysosome membranes.","evidence":"AlphaFold modeling plus cryo-FIB milling and cryo-ET of HeLa cells overexpressing full-length or truncated VPS13C with VAP","pmids":["35858323"],"confidence":"High","gaps":["Conformational regulation of the bridge not addressed","Relied on overexpression"]},{"year":2022,"claim":"Showed redundancy and breadth of lipid-droplet function by demonstrating VPS13A and VPS13C both regulate lipid droplet abundance at ER contacts.","evidence":"CRISPR-Cas9 knockout in U-2 OS cells with oleate-stimulated lipid droplet quantification","pmids":["36147729"],"confidence":"Medium","gaps":["Mechanistic basis of reduced lipid droplets unclear","Single readout"]},{"year":2024,"claim":"Defined lysosomal dysfunction in a disease-relevant human neuronal model and identified phospho-Rab10 as a lysosomal interactor in a stress response.","evidence":"Live-cell microscopy, lysosomal hydrolysis/acidification assays, and interaction assays in iPSC-derived dopaminergic neurons","pmids":["38358348"],"confidence":"High","gaps":["Phospho-Rab10 binding mechanism not structurally defined","Link between lysosomal defects and neurodegeneration not established"]},{"year":2025,"claim":"Established the inducible recruitment logic: damaged lysosomes recruit VPS13C from cytosol via Rab7 by releasing VAB-domain autoinhibition for ER-lysosome tethering.","evidence":"Live-cell imaging after lysosome damage, with genetic Rab7-dependence and VAB-domain accessibility analysis; LRRK2 kinetic comparison","pmids":["40211074"],"confidence":"High","gaps":["Identity of the damage signal releasing autoinhibition not defined here","Quantitative lipid delivery during repair not measured"]},{"year":2025,"claim":"Resolved the autoinhibited conformation at near-atomic resolution and identified calmodulin as a partner, implicating calcium-dependent control of lipid transfer.","evidence":"Cryo-EM of full-length VPS13C plus co-purification (preprint)","pmids":["41292763"],"confidence":"High","gaps":["Calmodulin/calcium regulatory mechanism not functionally validated","Single-lab preprint"]},{"year":2025,"claim":"Identified the ATG2C domain as a sensor of lysosomal lipid-packing defects and showed VPS13C contacts serve as platforms for OSBP/ORP-mediated ER wrapping during repair.","evidence":"Proteomics, conformational change analysis, directional lipid transport assays, and OSBP/ORP functional studies (preprint)","pmids":["bio_10.1101_2025.10.23.684214"],"confidence":"Medium","gaps":["Preprint not peer-reviewed","Direct demonstration of ATG2C lipid sensing in vivo limited"]},{"year":2025,"claim":"Demonstrated genetic redundancy between VPS13A and VPS13C in vivo, with combined loss being embryonic-lethal via defective erythropoiesis and innate immune activation.","evidence":"Vps13a/Vps13c double-knockout mice with erythroid differentiation and ISG/RIG-I/MDA5 expression analysis","pmids":["40956846"],"confidence":"High","gaps":["Shared substrate/site of redundant transfer not identified","Mechanism connecting lipid transport to erythropoiesis unresolved"]},{"year":2025,"claim":"Extended VPS13C function to host-pathogen biology, showing it regulates ER-Salmonella vacuole contacts, positioning, fission, and bacterial spread.","evidence":"BioID proximity labeling of SCV surface plus VPS13C knockdown/knockout functional readouts","pmids":["40953080"],"confidence":"Medium","gaps":["Whether lipid transfer per se drives SCV phenotypes not established","Single lab"]},{"year":null,"claim":"How the conformational gating of lipid transfer (VAB autoinhibition, ATG2C lipid sensing, calmodulin/calcium input) is integrated into a unified regulatory cycle, and how lipid-transfer defects mechanistically cause Parkinson's disease neurodegeneration, remain unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unified model linking damage sensing to transfer activation","Causal path from lysosomal lipid defect to dopaminergic neuron loss undefined","Physiological lipid cargo specificity not fully characterized"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0008289","term_label":"lipid binding","supporting_discovery_ids":[0,3,12]},{"term_id":"GO:0140104","term_label":"molecular carrier activity","supporting_discovery_ids":[0,12]},{"term_id":"GO:0140299","term_label":"molecular sensor activity","supporting_discovery_ids":[12]}],"localization":[{"term_id":"GO:0005783","term_label":"endoplasmic reticulum","supporting_discovery_ids":[0,3]},{"term_id":"GO:0005764","term_label":"lysosome","supporting_discovery_ids":[0,8,9]},{"term_id":"GO:0005768","term_label":"endosome","supporting_discovery_ids":[0,6]},{"term_id":"GO:0005811","term_label":"lipid droplet","supporting_discovery_ids":[0,7]},{"term_id":"GO:0005739","term_label":"mitochondrion","supporting_discovery_ids":[1]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[9]}],"pathway":[{"term_id":"GO:0005215","term_label":"transporter activity","supporting_discovery_ids":[0]},{"term_id":"R-HSA-9612973","term_label":"Autophagy","supporting_discovery_ids":[1,12]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[2,13]},{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[0,7]}],"complexes":[],"partners":["GAL12","TBC1D1","RAB7A","RAB10","CALM1","VAPA","OSBP","VPS13A"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q709C8","full_name":"Intermembrane lipid transfer protein VPS13C","aliases":["Vacuolar protein sorting-associated protein 13C"],"length_aa":3753,"mass_kda":422.4,"function":"Mediates the transfer of lipids between membranes at organelle contact sites (By similarity). Necessary for proper mitochondrial function and maintenance of mitochondrial transmembrane potential (PubMed:26942284). Involved in the regulation of PINK1/PRKN-mediated mitophagy in response to mitochondrial depolarization (PubMed:26942284)","subcellular_location":"Mitochondrion outer membrane; Lipid droplet; Endoplasmic reticulum membrane; Lysosome membrane; Late endosome membrane","url":"https://www.uniprot.org/uniprotkb/Q709C8/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/VPS13C","classification":"Not Classified","n_dependent_lines":0,"n_total_lines":1208,"dependency_fraction":0.0},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"BANF1","stoichiometry":0.2},{"gene":"CALM1","stoichiometry":0.2},{"gene":"CALM2","stoichiometry":0.2},{"gene":"CALM3","stoichiometry":0.2},{"gene":"DNAJC7","stoichiometry":0.2},{"gene":"LMAN1","stoichiometry":0.2},{"gene":"PIP4P1","stoichiometry":0.2},{"gene":"RAB11A","stoichiometry":0.2},{"gene":"RAB14","stoichiometry":0.2},{"gene":"RAB7A","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/VPS13C","total_profiled":1310},"omim":[{"mim_id":"621535","title":"SPINOCEREBELLAR ATAXIA 52; SCA52","url":"https://www.omim.org/entry/621535"},{"mim_id":"616840","title":"PARKINSON DISEASE 23, AUTOSOMAL RECESSIVE EARLY-ONSET; PARK23","url":"https://www.omim.org/entry/616840"},{"mim_id":"608879","title":"VACUOLAR PROTEIN SORTING 13 HOMOLOG C; VPS13C","url":"https://www.omim.org/entry/608879"},{"mim_id":"601035","title":"HETEROGENEOUS NUCLEAR RIBONUCLEOPROTEIN H1; HNRNPH1","url":"https://www.omim.org/entry/601035"},{"mim_id":"179490","title":"RAS-ASSOCIATED PROTEIN RAB3A; RAB3A","url":"https://www.omim.org/entry/179490"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/VPS13C"},"hgnc":{"alias_symbol":["FLJ20136","FLJ10381","KIAA1421","BLTP5C","PARK23"],"prev_symbol":[]},"alphafold":{"accession":"Q709C8","domains":[],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q709C8","model_url":"","pae_url":"","plddt_mean":null},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=VPS13C","jax_strain_url":"https://www.jax.org/strain/search?query=VPS13C"},"sequence":{"accession":"Q709C8","fasta_url":"https://rest.uniprot.org/uniprotkb/Q709C8.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q709C8/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q709C8"}},"corpus_meta":[{"pmid":"30093493","id":"PMC_30093493","title":"VPS13A and VPS13C are lipid transport proteins differentially localized at ER contact sites.","date":"2018","source":"The Journal of cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/30093493","citation_count":475,"is_preprint":false},{"pmid":"26942284","id":"PMC_26942284","title":"Loss of VPS13C Function in Autosomal-Recessive Parkinsonism Causes Mitochondrial Dysfunction and Increases PINK1/Parkin-Dependent Mitophagy.","date":"2016","source":"American journal of human genetics","url":"https://pubmed.ncbi.nlm.nih.gov/26942284","citation_count":352,"is_preprint":false},{"pmid":"35657605","id":"PMC_35657605","title":"ER-lysosome lipid transfer protein VPS13C/PARK23 prevents aberrant mtDNA-dependent STING signaling.","date":"2022","source":"The Journal of cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/35657605","citation_count":104,"is_preprint":false},{"pmid":"35858323","id":"PMC_35858323","title":"In situ architecture of the lipid transport protein VPS13C at ER-lysosome membrane contacts.","date":"2022","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/35858323","citation_count":83,"is_preprint":false},{"pmid":"28862745","id":"PMC_28862745","title":"Diagnostic exome sequencing in early-onset Parkinson's disease confirms VPS13C as a rare cause of autosomal-recessive Parkinson's disease.","date":"2018","source":"Clinical genetics","url":"https://pubmed.ncbi.nlm.nih.gov/28862745","citation_count":74,"is_preprint":false},{"pmid":"40211074","id":"PMC_40211074","title":"The bridge-like lipid transport protein VPS13C/PARK23 mediates ER-lysosome contacts following lysosome damage.","date":"2025","source":"Nature cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/40211074","citation_count":44,"is_preprint":false},{"pmid":"30376358","id":"PMC_30376358","title":"Upregulation of Circular RNA VPS13C-has-circ-001567 Promotes Ovarian Cancer Cell Proliferation and Invasion.","date":"2018","source":"Cancer biotherapy & 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a hydrophobic cavity capable of solubilizing and transporting glycerolipids between membranes in vitro. VPS13C binds to the ER and tethers it to late endosomes/lysosomes and lipid droplets, identifying it as a lipid transporter at ER-organelle contact sites.\",\n      \"method\": \"In vitro lipid transport reconstitution assay; Co-fractionation and co-localization by fluorescence microscopy; structural analysis of N-terminal domain\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro lipid transport reconstitution combined with structural analysis and localization experiments, replicated across multiple organelle contacts\",\n      \"pmids\": [\"30093493\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"VPS13C partly localizes to the outer membrane of mitochondria. Silencing of VPS13C causes lower mitochondrial membrane potential, mitochondrial fragmentation, increased respiration rates, and exacerbated PINK1/Parkin-dependent mitophagy, placing VPS13C upstream of this mitophagy pathway.\",\n      \"method\": \"siRNA-mediated knockdown in cell models; mitochondrial membrane potential assay; respiration measurements; fluorescence microscopy for mitochondrial morphology; PINK1/Parkin mitophagy pathway readouts\",\n      \"journal\": \"American journal of human genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean KD with multiple defined cellular phenotypes in a single lab; mitochondrial localization and pathway position established but not independently replicated at structural level\",\n      \"pmids\": [\"26942284\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"VPS13C depletion in HeLa cells causes accumulation of lysosomes with altered lipid profiles, including accumulation of di-22:6-BMP. Loss of VPS13C activates the cGAS-STING innate immune pathway through elevated cytosolic mitochondrial DNA combined with impaired lysosome-dependent degradation of activated STING.\",\n      \"method\": \"siRNA knockdown in HeLa cells; lipidomic profiling; cGAS-STING pathway activation assays; measurement of cytosolic mtDNA; STING degradation assays\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods (lipidomics, pathway assays, mtDNA measurement) in single lab\",\n      \"pmids\": [\"35657605\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Cryo-electron tomography of HeLa cells overexpressing VPS13C in situ, combined with AlphaFold-based full-length structural modeling, reveals that VPS13C adopts an ~30-nm rod with a continuous hydrophobic groove spanning its length. Rod-like densities bridging ER and endo/lysosome membranes were observed in situ, providing direct structural evidence for a bridge-like lipid transport mechanism.\",\n      \"method\": \"AlphaFold structural prediction; cryo-focused ion beam (cryo-FIB) milling; cryo-electron tomography (cryo-ET) in situ in HeLa cells overexpressing full-length or internally truncated VPS13C with VAP\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — cryo-ET in situ structural evidence combined with genetic truncation controls and full-length modeling, multiple orthogonal structural approaches\",\n      \"pmids\": [\"35858323\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"VPS13C is identified as a major binding partner of galectin-12. VPS13C is required for galectin-12 protein stability; knockdown of Vps13c markedly reduces galectin-12 steady-state levels by promoting its degradation through the lysosomal pathway, and impairs adipocyte differentiation.\",\n      \"method\": \"Co-immunoprecipitation/pulldown to identify VPS13C as galectin-12-binding protein; siRNA knockdown; lysosomal degradation assays; adipocyte differentiation assays\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP binding identification plus functional KD with defined phenotype (galectin-12 stability, adipogenesis), single lab\",\n      \"pmids\": [\"27073999\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"VPS13C interacts with TBC1D1 via its phosphotyrosine binding (PTB) domains in C2C12 myotubes. Depletion of VPS13C causes a post-transcriptional increase in cellular GLUT4 protein and enhanced cell surface GLUT4 levels in response to AMPK activation, specifically affecting GLUT4 homeostasis.\",\n      \"method\": \"Unbiased quantitative proteomics (mass spectrometry) to identify TBC1D1-interacting proteins; siRNA depletion; cell surface GLUT4 assay; western blotting\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — MS-based interaction identification plus KD with specific phenotypic readout (GLUT4 levels/trafficking), single lab\",\n      \"pmids\": [\"33087848\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Compound heterozygous missense mutations p.Trp395Cys and p.Ala444Pro in VPS13C abolish its endosomal/lysosomal localization when overexpressed in HeLa or SH-SY5Y cells, demonstrating that these residues are required for proper subcellular targeting.\",\n      \"method\": \"Overexpression of wild-type or mutant VPS13C in HeLa and SH-SY5Y cells; fluorescence microscopy to assess endosomal/lysosomal localization\",\n      \"journal\": \"Acta neuropathologica communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — localization assay with functional mutagenesis in two cell lines, single lab\",\n      \"pmids\": [\"33579389\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Loss of VPS13A or VPS13C in U-2 OS cells via CRISPR-Cas9 knockout results in reduced lipid droplet abundance under oleate-stimulated conditions, implicating both proteins in lipid droplet regulation at ER-lipid droplet contact sites.\",\n      \"method\": \"CRISPR-Cas9 knockout of VPS13A and VPS13C (exon 2 deletion); lipid droplet quantification under oleate stimulation\",\n      \"journal\": \"Contact (Thousand Oaks)\",\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\": 2024,\n      \"finding\": \"In human iPSC-derived dopaminergic neurons, loss of VPS13C disrupts lysosomal morphology and dynamics with increased inter-lysosomal contacts, impaired lysosomal motility and distribution, and defective lysosomal hydrolytic activity and acidification. Rab10 was identified as a phospho-dependent interactor of VPS13C on lysosomes; loss of VPS13C decreased phospho-Rab10-mediated lysosomal stress response.\",\n      \"method\": \"Live-cell microscopy in iPSC-derived dopaminergic neurons with VPS13C loss-of-function; lysosomal functional assays (hydrolytic activity, acidification); co-immunoprecipitation/interaction assays to identify phospho-Rab10 as VPS13C interactor\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — disease-relevant human neuronal model, multiple orthogonal functional readouts (morphology, motility, hydrolysis, acidification), plus binding partner identification, single lab with comprehensive approach\",\n      \"pmids\": [\"38358348\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Following lysosome membrane perturbation, VPS13C rapidly relocates from the cytosol to the lysosome surface where it tethers lysosome membranes to the ER. This recruitment depends on Rab7 and requires a signal at the damaged lysosome surface that releases an autoinhibited state of VPS13C, where the VAB domain is blocked from accessing lysosome-bound Rab7. LRRK2 is recruited to damaged lysosomes at much later stages and by different mechanisms.\",\n      \"method\": \"Live-cell fluorescence microscopy following lysosome damage induction; genetic approaches to demonstrate Rab7 dependence; functional analysis of VAB domain accessibility; comparison with LRRK2 recruitment kinetics\",\n      \"journal\": \"Nature cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — live imaging with multiple genetic and pharmacological perturbations, mechanistic dissection of VAB domain autoinhibition, published in peer-reviewed journal\",\n      \"pmids\": [\"40211074\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Cryo-EM structure of intact VPS13C at near-atomic resolution reveals a lipid-transfer-nonpermissive conformation where the built-in C-terminal VAB adaptor module blocks the end of the lipid transfer bridge, interfering with lipid delivery. Calmodulin was identified as a VPS13C binding partner, suggesting calcium-dependent regulation of VPS13C lipid transfer activity.\",\n      \"method\": \"Cryo-EM structure determination of full-length VPS13C; co-purification to identify calmodulin as binding partner\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — near-atomic cryo-EM structure of intact protein with mechanistic interpretation of autoinhibitory conformation; single lab preprint\",\n      \"pmids\": [\"41292763\"],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"VPS13C promotes ER-Salmonella-containing vacuole (SCV) contact formation, controls SCV positioning in host cells, regulates SCV morphology and fission, and facilitates cell-to-cell spread of S. Typhimurium, establishing VPS13C as a regulator of intracellular bacterial vacuole dynamics.\",\n      \"method\": \"BioID proximity labeling proteomics of SCV surface; functional knockdown/knockout studies of VPS13C with SCV morphology, fission, positioning, and bacterial spread readouts\",\n      \"journal\": \"PLoS pathogens\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — BioID identification plus functional studies with multiple cellular phenotype readouts, single lab\",\n      \"pmids\": [\"40953080\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"VPS13C's ATG2C domain acts as a sensor of damage-induced lipid packing defects at lysosomes, triggering a conformational change in the C-terminus upon lysosomal membrane damage. ER-lysosome contacts formed by VPS13C provide binding platforms for OSBP/ORPs to enable ER wrapping of damaged lysosomes. VPS13C is essential for large-scale ER-to-lysosome lipid delivery required for lysosomal repair.\",\n      \"method\": \"Unbiased proteomics; conformational change analysis; directional lipid transport chemical assay; OSBP/ORP co-localization and functional studies; lysosome damage and repair assays\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods in single lab preprint; mechanistic dissection of ATG2C domain sensing and lipid transfer directionality\",\n      \"pmids\": [\"bio_10.1101_2025.10.23.684214\"],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Vps13a/Vps13c double knockout (DKO) mice die at midgestation with defective embryonic erythropoiesis and innate immune activation (upregulation of ISGs, RIG-I, and MDA5), while single knockouts are viable. This genetic epistasis demonstrates partially redundant lipid transport functions between VPS13A and VPS13C despite their distinct subcellular localizations.\",\n      \"method\": \"CRISPR/genetic double knockout mouse model; embryonic lethality assessment; erythroid differentiation assays; innate immunity gene expression analysis\",\n      \"journal\": \"PLoS biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — clean double-KO mouse genetic epistasis with multiple mechanistic readouts (erythropoiesis, innate immunity activation), peer-reviewed publication\",\n      \"pmids\": [\"40956846\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Beta-cell-specific deletion of Vps13c in mice results in significantly increased glucose-stimulated intracellular free Ca2+ in islets from female knockout mice, suggesting impaired Ca2+ sensitivity of the insulin secretory machinery, though glucose-stimulated insulin secretion was not altered in vitro.\",\n      \"method\": \"Conditional knockout mice (floxed Vps13c x Ins1-Cre); OGTT; intracellular Ca2+ imaging in isolated islets; glucose-stimulated insulin secretion assay\",\n      \"journal\": \"American journal of physiology. Endocrinology and metabolism\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean conditional KO with Ca2+ imaging phenotype, but effect was sex-specific and modest; single lab\",\n      \"pmids\": [\"27329800\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"VPS13C is a bridge-like lipid transfer protein that localizes at ER contact sites with late endosomes/lysosomes and lipid droplets, where it transports bulk glycerolipids between adjacent membranes through a continuous hydrophobic groove spanning its ~30-nm rod-like structure; upon lysosome damage, VPS13C is recruited from the cytosol to damaged lysosomes in a Rab7-dependent manner by releasing a VAB-domain-mediated autoinhibited conformation, facilitating ER-lysosome tethering, large-scale lipid delivery for lysosomal repair, and recruitment of OSBP/ORP proteins, while loss of VPS13C causes lysosomal dysfunction, altered lipid profiles, cGAS-STING innate immune activation via cytosolic mtDNA, and exacerbated PINK1/Parkin-dependent mitophagy, collectively linking its lipid transport function to Parkinson's disease pathogenesis.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"VPS13C is a bridge-like lipid transfer protein that operates at endoplasmic reticulum membrane contact sites, where it physically tethers the ER to late endosomes/lysosomes and lipid droplets and conveys bulk glycerolipids between the apposed bilayers [#0]. Structural work shows the protein folds into an ~30-nm rod traversed by a continuous hydrophobic groove, with rod-like densities seen bridging ER and endo/lysosome membranes in situ, providing a direct physical basis for membrane-to-membrane lipid transfer [#3]. The lipid-transfer reaction is conformationally gated: the C-terminal VAB adaptor module folds back to block the end of the transfer bridge in an autoinhibited, transfer-nonpermissive state [#10], and following lysosome membrane damage VPS13C is rapidly recruited from the cytosol to the lysosome surface in a Rab7-dependent manner that relieves this autoinhibition and establishes ER-lysosome contacts for large-scale lipid delivery and lysosomal repair [#9]. Loss of VPS13C produces lysosomes with altered lipid profiles and defective hydrolytic activity, motility, and acidification, and triggers cGAS-STING innate immune activation through elevated cytosolic mitochondrial DNA and impaired STING degradation [#2, #8]. VPS13C also localizes partly to mitochondria and acts upstream of PINK1/Parkin-dependent mitophagy [#1], and partially redundant lipid-transport functions with VPS13A are essential for embryonic erythropoiesis, as Vps13a/Vps13c double-knockout mice die at midgestation with innate immune activation [#13]. Compound heterozygous missense mutations that abolish endolysosomal targeting link these functions to disease [#6]. The protein engages additional partners and contexts—Rab10 and phospho-Rab10 lysosomal stress signaling [#8], OSBP/ORP recruitment for ER wrapping of damaged lysosomes [#12], TBC1D1/GLUT4 homeostasis [#5], galectin-12 stability and adipogenesis [#4], and ER-Salmonella vacuole dynamics [#11].\",\n  \"teleology\": [\n    {\n      \"year\": 2016,\n      \"claim\": \"Established a mitochondrial connection by placing VPS13C upstream of a defined quality-control pathway, providing the first functional handle on its cellular role.\",\n      \"evidence\": \"siRNA knockdown with membrane potential, respiration, morphology, and PINK1/Parkin mitophagy readouts in cell models\",\n      \"pmids\": [\"26942284\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Does not establish direct molecular activity at mitochondria\", \"Mitochondrial localization not confirmed at structural level\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Identified the first direct binding partner (galectin-12) and a role in protein stability and adipocyte differentiation, broadening VPS13C beyond mitochondria.\",\n      \"evidence\": \"Co-IP/pulldown to identify galectin-12 binding, plus siRNA knockdown and lysosomal degradation/adipogenesis assays\",\n      \"pmids\": [\"27073999\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism linking VPS13C to galectin-12 degradation unresolved\", \"Relationship to lipid transfer function unclear\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Defined the core molecular activity—solubilization and transfer of glycerolipids between membranes—and identified VPS13C as a tether at ER-organelle contact sites.\",\n      \"evidence\": \"In vitro lipid transport reconstitution, co-fractionation/co-localization microscopy, and N-terminal structural analysis\",\n      \"pmids\": [\"30093493\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Full-length architecture not resolved\", \"Directionality and regulation of transfer not addressed\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Connected VPS13C loss to lysosomal lipid abnormalities and to cGAS-STING innate immune activation, linking lipid transport to immune signaling.\",\n      \"evidence\": \"siRNA knockdown in HeLa with lipidomics, cytosolic mtDNA measurement, and cGAS-STING/STING degradation assays\",\n      \"pmids\": [\"35657605\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Causal chain from lipid defect to mtDNA release not fully dissected\", \"Single cell line\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Provided direct in situ structural evidence that VPS13C is a ~30-nm rod with a continuous hydrophobic groove physically bridging ER and endo/lysosome membranes.\",\n      \"evidence\": \"AlphaFold modeling plus cryo-FIB milling and cryo-ET of HeLa cells overexpressing full-length or truncated VPS13C with VAP\",\n      \"pmids\": [\"35858323\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Conformational regulation of the bridge not addressed\", \"Relied on overexpression\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Showed redundancy and breadth of lipid-droplet function by demonstrating VPS13A and VPS13C both regulate lipid droplet abundance at ER contacts.\",\n      \"evidence\": \"CRISPR-Cas9 knockout in U-2 OS cells with oleate-stimulated lipid droplet quantification\",\n      \"pmids\": [\"36147729\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanistic basis of reduced lipid droplets unclear\", \"Single readout\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Defined lysosomal dysfunction in a disease-relevant human neuronal model and identified phospho-Rab10 as a lysosomal interactor in a stress response.\",\n      \"evidence\": \"Live-cell microscopy, lysosomal hydrolysis/acidification assays, and interaction assays in iPSC-derived dopaminergic neurons\",\n      \"pmids\": [\"38358348\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Phospho-Rab10 binding mechanism not structurally defined\", \"Link between lysosomal defects and neurodegeneration not established\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Established the inducible recruitment logic: damaged lysosomes recruit VPS13C from cytosol via Rab7 by releasing VAB-domain autoinhibition for ER-lysosome tethering.\",\n      \"evidence\": \"Live-cell imaging after lysosome damage, with genetic Rab7-dependence and VAB-domain accessibility analysis; LRRK2 kinetic comparison\",\n      \"pmids\": [\"40211074\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Identity of the damage signal releasing autoinhibition not defined here\", \"Quantitative lipid delivery during repair not measured\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Resolved the autoinhibited conformation at near-atomic resolution and identified calmodulin as a partner, implicating calcium-dependent control of lipid transfer.\",\n      \"evidence\": \"Cryo-EM of full-length VPS13C plus co-purification (preprint)\",\n      \"pmids\": [\"41292763\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Calmodulin/calcium regulatory mechanism not functionally validated\", \"Single-lab preprint\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Identified the ATG2C domain as a sensor of lysosomal lipid-packing defects and showed VPS13C contacts serve as platforms for OSBP/ORP-mediated ER wrapping during repair.\",\n      \"evidence\": \"Proteomics, conformational change analysis, directional lipid transport assays, and OSBP/ORP functional studies (preprint)\",\n      \"pmids\": [\"bio_10.1101_2025.10.23.684214\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Preprint not peer-reviewed\", \"Direct demonstration of ATG2C lipid sensing in vivo limited\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Demonstrated genetic redundancy between VPS13A and VPS13C in vivo, with combined loss being embryonic-lethal via defective erythropoiesis and innate immune activation.\",\n      \"evidence\": \"Vps13a/Vps13c double-knockout mice with erythroid differentiation and ISG/RIG-I/MDA5 expression analysis\",\n      \"pmids\": [\"40956846\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Shared substrate/site of redundant transfer not identified\", \"Mechanism connecting lipid transport to erythropoiesis unresolved\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Extended VPS13C function to host-pathogen biology, showing it regulates ER-Salmonella vacuole contacts, positioning, fission, and bacterial spread.\",\n      \"evidence\": \"BioID proximity labeling of SCV surface plus VPS13C knockdown/knockout functional readouts\",\n      \"pmids\": [\"40953080\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether lipid transfer per se drives SCV phenotypes not established\", \"Single lab\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How the conformational gating of lipid transfer (VAB autoinhibition, ATG2C lipid sensing, calmodulin/calcium input) is integrated into a unified regulatory cycle, and how lipid-transfer defects mechanistically cause Parkinson's disease neurodegeneration, remain unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unified model linking damage sensing to transfer activation\", \"Causal path from lysosomal lipid defect to dopaminergic neuron loss undefined\", \"Physiological lipid cargo specificity not fully characterized\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0008289\", \"supporting_discovery_ids\": [0, 3, 12]},\n      {\"term_id\": \"GO:0140104\", \"supporting_discovery_ids\": [0, 12]},\n      {\"term_id\": \"GO:0140299\", \"supporting_discovery_ids\": [12]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005783\", \"supporting_discovery_ids\": [0, 3]},\n      {\"term_id\": \"GO:0005764\", \"supporting_discovery_ids\": [0, 8, 9]},\n      {\"term_id\": \"GO:0005768\", \"supporting_discovery_ids\": [0, 6]},\n      {\"term_id\": \"GO:0005811\", \"supporting_discovery_ids\": [0, 7]},\n      {\"term_id\": \"GO:0005739\", \"supporting_discovery_ids\": [1]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [9]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"GO:0005215\", \"supporting_discovery_ids\": [0]},\n      {\"term_id\": \"R-HSA-9612973\", \"supporting_discovery_ids\": [1, 12]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [2, 13]},\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [0, 7]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"GAL12\", \"TBC1D1\", \"RAB7A\", \"RAB10\", \"CALM1\", \"VAPA\", \"OSBP\", \"VPS13A\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":7,"faith_pct":100.0}}