VPS50

VPS50 is the defining subunit of the endosome-associated recycling protein (EARP) complex, a heterotetramer it forms with the GARP-shared subunits VPS51, VPS52, and VPS53, and it functions in endocytic recycling and vesicle acidification (PMID:34037727). Within the complex VPS50 is structurally required for partner stability: its loss in patient fibroblasts reduces VPS53 and depletes VPS52 protein levels (PMID:34037727, PMID:38876772). Functionally, EARP/VPS50 drives recycling of internalized transferrin receptors back to the plasma membrane, and a missense variant (p.Gly169Val) that weakens the VPS50–VPS53 interaction delays this recycling as a loss-of-function (PMID:30828385, PMID:34037727). In neurons, VPS50 associates with synaptic and dense-core vesicles and acts as an accessory factor recruiting the V-ATPase V1 domain to synaptic vesicles, thereby controlling vesicle acidification, synaptic transmission and plasticity; its loss impairs neurotransmission and produces cognitive deficits without altering vesicle number (PMID:26948874, PMID:38926759). In epithelial cells VPS50 establishes hepatocyte polarity, with its loss mislocalizing gamma-glutamyltransferase from bile canaliculi to basolateral membranes and disrupting tight junctions (PMID:34037727).

1. 2016 Medium

   Established the first cellular role for VPS50 by linking it to synaptic and dense-core vesicles and to vesicle acidification, framing it as a presynaptic regulator.

   Evidence C. elegans genetics, behavioral assays, subcellular fractionation, and murine homolog expression in neurons

   PMID:26948874

   Open questions at the time

   • V-ATPase assembly link proposed, not biochemically reconstituted
   • molecular mechanism connecting VPS50 to acidification not defined
   • human/mammalian functional role not yet shown
2. 2019 Medium

   Defined VPS50 as an EARP subunit required for transferrin receptor recycling and showed a disease-associated missense variant impairs recycling by altering the VPS50–VPS53 interaction.

   Evidence In vitro transferrin recycling assay, VPS50–VPS53 co-immunoprecipitation, and zebrafish knockdown-rescue

   PMID:30828385

   Open questions at the time

   • single-lab study
   • full EARP complex composition not resolved here
   • no structural basis for the VPS50–VPS53 interface
3. 2021 High

   Positioned VPS50 as the unique EARP subunit whose loss destabilizes VPS52/VPS53 and showed EARP function extends to establishing epithelial cell polarity in hepatocytes.

   Evidence Patient-derived fibroblast Western blot, TfR recycling assay, and light/electron microscopy of liver tissue

   PMID:34037727

   Open questions at the time

   • mechanism linking endosomal recycling to tight-junction/polarity establishment unresolved
   • cargo beyond TfR and GGT not mapped
4. 2024 Medium

   Confirmed in an independent patient cohort that VPS50 is required for stability of the other EARP subunits, reducing VPS53 and abolishing VPS52.

   Evidence Western blot of patient fibroblasts with biallelic loss-of-function variants and long-read genome sequencing

   PMID:38876772

   Open questions at the time

   • single study replicating prior finding
   • does not address whether destabilization is transcriptional or post-translational
5. 2024 High

   Provided the mechanistic basis for the acidification phenotype by showing VPS50 recruits the V-ATPase V1 domain to synaptic vesicles, linking it to synaptic transmission, plasticity, and cognition.

   Evidence CRISPR/Cas9 KO in cultured cortical neurons and in vivo hippocampus, V-ATPase V1 immunolocalization, electrophysiology, and behavioral assays

   PMID:38926759

   Open questions at the time

   • direct physical interaction between VPS50 and V-ATPase V1 not biochemically demonstrated
   • how endosomal recycling activity connects to vesicular V1 recruitment unclear

• How EARP/VPS50 recognizes specific cargo and physically couples the V-ATPase V1 domain to vesicle membranes, and whether reported DNA-damage signaling effects reflect a genuine EARP-independent role, remain unresolved.
• no reconstituted EARP–V-ATPase interaction
• no structural model of the EARP tetramer
• cargo-recognition determinants unknown