VPS26C

VPS26C is a subunit of the Retriever endosomal recycling complex that, together with VPS35L and VPS29, selectively returns internalized transmembrane cargo from endosomes to the plasma membrane (PMID:36353989). In hepatocytes, VPS26C-dependent Retriever activity specifically recycles LRP1—but not LDLR—to the cell surface, and liver-specific VPS26C ablation in mice delays postprandial triglyceride clearance and raises plasma triglycerides, defining a role in lipoprotein metabolism (PMID:36353989). The complex acts with cargo selectivity that distinguishes it from the shared CCC-associated subunit VPS35L, which is required for surface expression of both LRP1 and LDLR (PMID:36353989). VPS26C extends this recycling function to other cargo: it directly binds internalized SLC38A1 and sorts it into the recycling pathway, sustaining surface SLC38A1 levels, enhancing glutamine uptake, and promoting temozolomide resistance in glioblastoma cells (PMID:35187626).

1. 2019 Low

   Establishing whether VPS26C is biologically essential in humans, a homozygous loss-of-function variant was linked to a multisystem developmental disorder, implicating Retriever-mediated recycling in normal growth and neurodevelopment.

   Evidence Genome sequencing, transcript quantification, and co-segregation in two affected cousins

   PMID:31845315

   Open questions at the time

   • Single family with no functional rescue; causation not mechanistically demonstrated
   • No molecular cargo or pathway connected to the clinical phenotype
   • Tissue-level mechanism underlying skeletal and neurodevelopmental defects unknown
2. 2022 Medium

   Identifying a specific cargo of VPS26C, the protein was shown to directly bind internalized SLC38A1 and route it back to the surface, defining VPS26C as a determinant of nutrient transporter abundance and a driver of glutamine-fueled drug resistance.

   Evidence Co-IP, plasma-membrane proteomics, immunofluorescence, and silencing/rescue in MGMT-deficient GBM cells plus orthotopic mouse model

   PMID:35187626

   Open questions at the time

   • Single lab; binding interface and sorting signal on SLC38A1 not mapped
   • Whether recycling requires the full Retriever complex in this context not tested
   • Generality beyond glioblastoma not established
3. 2022 High

   Placing VPS26C within the Retriever complex in vivo, liver-specific knockout demonstrated cargo-selective recycling of LRP1 and a defined metabolic phenotype, distinguishing Retriever-specific from CCC-shared subunit functions.

   Evidence Somatic CRISPR/Cas9 liver-specific KO in mice, surface protein quantification, plasma lipid measurements, and VPS26C-deficient hepatoma cell experiments

   PMID:36353989

   Open questions at the time

   • Structural basis for LRP1 versus LDLR cargo selectivity not resolved
   • Recognition motif on LRP1 that VPS26C reads not identified
   • Full spectrum of VPS26C-dependent cargo across tissues unknown

• How VPS26C selects its diverse cargo (LRP1, SLC38A1) and the structural rules governing Retriever cargo specificity remain undefined.
• No structural model of VPS26C cargo recognition
• Mechanism of endosomal recruitment of the Retriever complex via VPS26C unresolved
• Link between molecular cargo handling and the human disease phenotype not established