Affinage

VPS13C

Intermembrane lipid transfer protein VPS13C · UniProt Q709C8

Length
3753 aa
Mass
422.4 kDa
Annotated
2026-06-11
30 papers in source corpus 15 papers cited in narrative 15 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 7/7 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

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).

Mechanistic history

Synthesis pass · year-by-year structured walk · 12 steps
  1. 2016 Medium

    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

    PMID:26942284

    Open questions at the time
    • Does not establish direct molecular activity at mitochondria
    • Mitochondrial localization not confirmed at structural level
  2. 2016 Medium

    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

    PMID:27073999

    Open questions at the time
    • Mechanism linking VPS13C to galectin-12 degradation unresolved
    • Relationship to lipid transfer function unclear
  3. 2018 High

    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

    PMID:30093493

    Open questions at the time
    • Full-length architecture not resolved
    • Directionality and regulation of transfer not addressed
  4. 2022 Medium

    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

    PMID:35657605

    Open questions at the time
    • Causal chain from lipid defect to mtDNA release not fully dissected
    • Single cell line
  5. 2022 High

    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

    PMID:35858323

    Open questions at the time
    • Conformational regulation of the bridge not addressed
    • Relied on overexpression
  6. 2022 Medium

    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

    PMID:36147729

    Open questions at the time
    • Mechanistic basis of reduced lipid droplets unclear
    • Single readout
  7. 2024 High

    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

    PMID:38358348

    Open questions at the time
    • Phospho-Rab10 binding mechanism not structurally defined
    • Link between lysosomal defects and neurodegeneration not established
  8. 2025 High

    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

    PMID:40211074

    Open questions at the time
    • Identity of the damage signal releasing autoinhibition not defined here
    • Quantitative lipid delivery during repair not measured
  9. 2025 High

    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)

    PMID:41292763

    Open questions at the time
    • Calmodulin/calcium regulatory mechanism not functionally validated
    • Single-lab preprint
  10. 2025 Medium

    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)

    PMID:bio_10.1101_2025.10.23.684214

    Open questions at the time
    • Preprint not peer-reviewed
    • Direct demonstration of ATG2C lipid sensing in vivo limited
  11. 2025 High

    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

    PMID:40956846

    Open questions at the time
    • Shared substrate/site of redundant transfer not identified
    • Mechanism connecting lipid transport to erythropoiesis unresolved
  12. 2025 Medium

    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

    PMID:40953080

    Open questions at the time
    • Whether lipid transfer per se drives SCV phenotypes not established
    • Single lab

Open questions

Synthesis pass · forward-looking unresolved questions
  • 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.
  • 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

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0008289 lipid binding 3 GO:0140104 molecular carrier activity 2 GO:0140299 molecular sensor activity 1
Localization
GO:0005764 lysosome 3 GO:0005768 endosome 2 GO:0005783 endoplasmic reticulum 2 GO:0005811 lipid droplet 2 GO:0005739 mitochondrion 1 GO:0005829 cytosol 1
Pathway
R-HSA-1430728 Metabolism 2 R-HSA-168256 Immune System 2 R-HSA-9612973 Autophagy 2 GO:0005215 transporter activity 1
Partners
CALM1GAL12OSBPRAB10RAB7ATBC1D1VAPAVPS13A

Evidence

Reading pass · 15 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2018 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. In vitro lipid transport reconstitution assay; Co-fractionation and co-localization by fluorescence microscopy; structural analysis of N-terminal domain The Journal of cell biology High 30093493
2016 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. siRNA-mediated knockdown in cell models; mitochondrial membrane potential assay; respiration measurements; fluorescence microscopy for mitochondrial morphology; PINK1/Parkin mitophagy pathway readouts American journal of human genetics Medium 26942284
2022 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. siRNA knockdown in HeLa cells; lipidomic profiling; cGAS-STING pathway activation assays; measurement of cytosolic mtDNA; STING degradation assays The Journal of cell biology Medium 35657605
2022 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. 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 Proceedings of the National Academy of Sciences of the United States of America High 35858323
2016 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. Co-immunoprecipitation/pulldown to identify VPS13C as galectin-12-binding protein; siRNA knockdown; lysosomal degradation assays; adipocyte differentiation assays PloS one Medium 27073999
2020 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. Unbiased quantitative proteomics (mass spectrometry) to identify TBC1D1-interacting proteins; siRNA depletion; cell surface GLUT4 assay; western blotting Scientific reports Medium 33087848
2021 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. Overexpression of wild-type or mutant VPS13C in HeLa and SH-SY5Y cells; fluorescence microscopy to assess endosomal/lysosomal localization Acta neuropathologica communications Medium 33579389
2022 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. CRISPR-Cas9 knockout of VPS13A and VPS13C (exon 2 deletion); lipid droplet quantification under oleate stimulation Contact (Thousand Oaks) Medium 36147729
2024 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. 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 The Journal of cell biology High 38358348
2025 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. 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 Nature cell biology High 40211074
2025 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. Cryo-EM structure determination of full-length VPS13C; co-purification to identify calmodulin as binding partner bioRxivpreprint High 41292763
2025 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. BioID proximity labeling proteomics of SCV surface; functional knockdown/knockout studies of VPS13C with SCV morphology, fission, positioning, and bacterial spread readouts PLoS pathogens Medium 40953080
2025 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. Unbiased proteomics; conformational change analysis; directional lipid transport chemical assay; OSBP/ORP co-localization and functional studies; lysosome damage and repair assays bioRxivpreprint Medium bio_10.1101_2025.10.23.684214
2025 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. CRISPR/genetic double knockout mouse model; embryonic lethality assessment; erythroid differentiation assays; innate immunity gene expression analysis PLoS biology High 40956846
2016 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. Conditional knockout mice (floxed Vps13c x Ins1-Cre); OGTT; intracellular Ca2+ imaging in isolated islets; glucose-stimulated insulin secretion assay American journal of physiology. Endocrinology and metabolism Medium 27329800

Source papers

Stage 0 corpus · 30 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2018 VPS13A and VPS13C are lipid transport proteins differentially localized at ER contact sites. The Journal of cell biology 475 30093493
2016 Loss of VPS13C Function in Autosomal-Recessive Parkinsonism Causes Mitochondrial Dysfunction and Increases PINK1/Parkin-Dependent Mitophagy. American journal of human genetics 352 26942284
2022 ER-lysosome lipid transfer protein VPS13C/PARK23 prevents aberrant mtDNA-dependent STING signaling. The Journal of cell biology 104 35657605
2022 In situ architecture of the lipid transport protein VPS13C at ER-lysosome membrane contacts. Proceedings of the National Academy of Sciences of the United States of America 83 35858323
2018 Diagnostic exome sequencing in early-onset Parkinson's disease confirms VPS13C as a rare cause of autosomal-recessive Parkinson's disease. Clinical genetics 74 28862745
2025 The bridge-like lipid transport protein VPS13C/PARK23 mediates ER-lysosome contacts following lysosome damage. Nature cell biology 44 40211074
2018 Upregulation of Circular RNA VPS13C-has-circ-001567 Promotes Ovarian Cancer Cell Proliferation and Invasion. Cancer biotherapy & radiopharmaceuticals 40 30376358
2016 Identification of VPS13C as a Galectin-12-Binding Protein That Regulates Galectin-12 Protein Stability and Adipogenesis. PloS one 40 27073999
2021 Contribution of rare homozygous and compound heterozygous VPS13C missense mutations to dementia with Lewy bodies and Parkinson's disease. Acta neuropathologica communications 37 33579389
2011 The diabetogenic VPS13C/C2CD4A/C2CD4B rs7172432 variant impairs glucose-stimulated insulin response in 5,722 non-diabetic Danish individuals. Diabetologia 27 21249489
2022 VPS13A and VPS13C Influence Lipid Droplet Abundance. Contact (Thousand Oaks (Ventura County, Calif.)) 25 36147729
2024 VPS13C regulates phospho-Rab10-mediated lysosomal function in human dopaminergic neurons. The Journal of cell biology 23 38358348
2020 Mutation screening and burden analysis of VPS13C in Chinese patients with early-onset Parkinson's disease. Neurobiology of aging 22 32507414
2021 VPS13C-associated Parkinson's disease: Two novel cases and review of the literature. Parkinsonism & related disorders 18 34875562
2020 TBC1D1 interacting proteins, VPS13A and VPS13C, regulate GLUT4 homeostasis in C2C12 myotubes. Scientific reports 16 33087848
2016 Changes in the expression of the type 2 diabetes-associated gene VPS13C in the β-cell are associated with glucose intolerance in humans and mice. American journal of physiology. Endocrinology and metabolism 16 27329800
2006 Brain-specific transcript variants of 5' and 3' ends of mouse VPS13A and VPS13C. Biochemical and biophysical research communications 12 17196930
2023 Downregulation of VPS13C promotes cisplatin resistance in cervical cancer by upregulating GSTP1. iScience 8 37520723
2025 Lysosome damage triggers acute formation of ER to lysosomes membrane tethers mediated by the bridge-like lipid transport protein VPS13C. bioRxiv : the preprint server for biology 7 38895395
2021 Circ-VPS13C enhances cisplatin resistance in ovarian cancer via modulating the miR-106b-5p/YWHAZ axis. Archives of medical science : AMS 5 39439709
2025 Impaired hematopoiesis and embryonic lethality at midgestation of mice lacking both lipid transfer proteins VPS13A and VPS13C. PLoS biology 3 40956846
2024 VPS13C and STING expression in neuropsychiatric systemic lupus erythematosus: unveiling an unbreached territory. Lupus science & medicine 3 39306342
2025 Insights into the regulation of VPS13 family bridge-like lipid transfer proteins from the structure of VPS13C. bioRxiv : the preprint server for biology 2 41292763
2025 Proximity labelling reveals VPS13C as a regulator of Salmonella-containing vacuole fission. PLoS pathogens 1 40953080
2021 Association between VPS13C rs2414739 polymorphism and Parkinson's disease risk: A meta-analysis. Neuroscience letters 1 33838259
2026 Two novel variants of VPS13C gene related Parkinsonism: A case report and literature review. Medicine 0 41517720
2026 Novel associations of VPS13C with phenotype and conversion of idiopathic REM sleep behavior disorder. NPJ Parkinson's disease 0 41981001
2025 Defect in hematopoiesis and embryonic lethality at midgestation of Vps13a/Vps13c double knockout mice. bioRxiv : the preprint server for biology 0 40463036
2025 VPS13C heterozygous loss of function as a modifier for suboptimal response to levodopa in Parkinson's disease. Parkinsonism & related disorders 0 41006073
2024 Derivation of induced pluripotent stem cell TUSMi013-A from a 66-year-old Chinese Han Parkinson's disease patient carrying VPS13C and TBP mutations. Stem cell research 0 39914017

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