VPS13C

VPS13C is a bridge-like lipid transfer protein that forms an ~30-nm rod with a continuous hydrophobic groove, spanning ER contact sites with late endosomes/lysosomes, lipid droplets, and mitochondria to mediate bulk glycerolipid transport between adjacent organelle membranes (PMID:30093493, PMID:35858323). VPS13C exists in an autoinhibited conformation in which the C-terminal VAB domain occludes the lipid-transfer groove; lysosome damage triggers Rab7-dependent release of this autoinhibition and rapid recruitment of VPS13C to damaged lysosomes, where it tethers the ER and facilitates large-scale lipid delivery for membrane repair (PMID:40211074, PMID:35858323). Loss of VPS13C disrupts lysosomal lipid homeostasis—including accumulation of di-22:6-BMP—impairs lysosomal acidification and hydrolytic function in dopaminergic neurons via a phospho-Rab10-dependent mechanism, elevates cytosolic mitochondrial DNA leading to cGAS-STING innate immune activation, and enhances PINK1/Parkin-dependent mitophagy (PMID:35657605, PMID:38358348, PMID:26942284). VPS13C is partially functionally redundant with VPS13A, as combined loss in mice causes embryonic lethality with defective erythroid differentiation and innate immune activation (PMID:40956846).

1. 2016 High

   VPS13C was placed upstream of the PINK1/Parkin mitophagy pathway, establishing that its loss disrupts mitochondrial membrane potential and morphology and exacerbates mitophagy—revealing its first direct link to organelle homeostasis and Parkinson's disease biology.

   Evidence siRNA knockdown with mitochondrial membrane potential, morphology, and mitophagy flux assays in human cells

   PMID:26942284

   Open questions at the time

   • Mechanism by which VPS13C maintains mitochondrial membrane potential was unknown
   • Whether the mitochondrial phenotype is primary or secondary to ER–endolysosome lipid transfer defects was unclear
2. 2018 High

   Structural and biochemical reconstitution demonstrated that VPS13C functions as a lipid transporter: its N-terminal tubular domain solubilizes and shuttles glycerolipids between membranes, and it tethers the ER to endolysosomes and lipid droplets—establishing the molecular mechanism as bridge-mediated bulk lipid transfer.

   Evidence In vitro lipid transport assay with purified N-terminal domain, structural analysis, and cell-based co-localization/tethering assays

   PMID:30093493

   Open questions at the time

   • Full-length structure and how the complete groove operates were unresolved
   • Directionality and specificity of lipid species transferred in cells remained unknown
3. 2021 Medium

   Disease-associated missense mutations (p.Trp395Cys, p.Ala444Pro) were shown to abolish endosomal/lysosomal localization of VPS13C, directly linking loss of proper subcellular targeting to pathogenic variants.

   Evidence Overexpression of WT vs. mutant VPS13C with fluorescence microscopy in HeLa/SH-SY5Y cells

   PMID:33579389

   Open questions at the time

   • Overexpression system may not recapitulate endogenous localization dynamics
   • Functional consequences of mislocalization on lipid transfer were not measured
4. 2022 High

   Two advances defined VPS13C architecture and downstream consequences of its loss: cryo-ET revealed the full ~30-nm bridge spanning ER–endolysosome contacts with VAP as the ER anchor, while lipidomics showed that VPS13C depletion alters lysosomal lipid composition and activates cGAS-STING signaling through cytosolic mitochondrial DNA release and defective STING degradation.

   Evidence Cryo-FIB milling and cryo-ET of VPS13C-overexpressing cells with truncation mutants; siRNA knockdown with lipidomics, mtDNA cytosolic release assays, and cGAS-STING activation readouts

   PMID:35657605 PMID:35858323

   Open questions at the time

   • Whether cGAS-STING activation is a direct consequence of lysosomal lipid imbalance or mitochondrial dysfunction was not dissected
   • Lipid droplet contact site function was phenotypically characterized only by droplet abundance
5. 2024 High

   In disease-relevant iPSC-derived dopaminergic neurons, VPS13C was shown to interact with phospho-Rab10 on lysosomes and to be required for lysosomal morphology, motility, acidification, and the phospho-Rab10-mediated stress response—connecting lipid transfer to neuronal lysosomal quality control.

   Evidence CRISPR KO of VPS13C in iPSC-derived dopaminergic neurons with Co-IP for Rab10 interaction and live-cell lysosomal functional assays

   PMID:38358348

   Open questions at the time

   • Whether phospho-Rab10 regulates VPS13C lipid transfer activity or merely co-localizes was not determined
   • Contribution of VPS13C loss to dopaminergic neuron survival in vivo was not tested
6. 2025 High

   A convergent set of studies resolved VPS13C's activation mechanism: lysosome damage triggers Rab7-dependent release of VAB-domain autoinhibition, enabling rapid recruitment to damaged lysosomes where VPS13C tethers the ER and provides platforms for OSBP/ORP-mediated lipid delivery and membrane repair. Near-atomic cryo-EM confirmed the autoinhibited conformation and identified calmodulin as a regulatory binding partner.

   Evidence Live-cell imaging with LLOMe-induced lysosome damage, Rab7 KO/dominant-negative perturbation, VAB-domain mutagenesis, cryo-EM of full-length VPS13C, calmodulin co-purification

   PMID:40211074 PMID:41292763

   Open questions at the time

   • Calmodulin's role identified in preprint and not yet peer-reviewed
   • Precise lipid species delivered during lysosome repair and the role of calcium in releasing autoinhibition in vivo are uncharacterized
7. 2025 High

   Double knockout of VPS13A and VPS13C in mice demonstrated embryonic lethality, defective erythropoiesis, and innate immune activation, establishing partial functional redundancy between these paralogs in maintaining organelle membrane lipid homeostasis.

   Evidence Vps13a/Vps13c double KO mouse embryonic phenotype analysis with erythroid differentiation assays and ISG profiling

   PMID:40956846

   Open questions at the time

   • Single Vps13c KO mouse phenotype in neurons was not reported in this study
   • Relative contributions of each paralog to specific organelle contact sites remain unresolved
8. 2025 Medium

   VPS13C was co-opted during Salmonella infection: it promotes ER–SCV contacts, controls vacuole morphology and fission, and facilitates bacterial cell-to-cell spread, extending VPS13C's role to host–pathogen interactions.

   Evidence BioID proximity proteomics, VPS13C KD/KO, live-cell imaging of SCV dynamics, bacterial spread assays

   PMID:40953080

   Open questions at the time

   • Whether Salmonella actively recruits VPS13C or exploits constitutive ER contacts is unclear
   • Relevance to in vivo infection not established

• Key unresolved questions include the identity and directionality of specific lipid species transferred by VPS13C in vivo, how calmodulin and calcium signaling regulate the autoinhibition–activation cycle, and whether VPS13C loss is sufficient to cause dopaminergic neurodegeneration in mammalian models.
• No in vivo lipid flux measurements through VPS13C
• Calmodulin regulation awaits peer-reviewed validation and in vivo testing
• Conditional neuron-specific VPS13C KO mouse phenotype not reported