VPS52

VPS52 is a core subunit of the tetrameric GARP (Golgi-Associated Retrograde Protein) tethering complex (Vps51/52/53/54) that mediates retrograde vesicular transport from early and late endosomes back to the trans-Golgi network, with Vps51p linking the Vps52/53/54 subcomplex to the late-Golgi t-SNARE Tlg1p to couple tethering with membrane fusion (PMID:12686613). As part of GARP, VPS52 acts as a Rab6 effector required for Rab6-dependent secretory cargo trafficking; its loss phenocopies Rab6 knockout, attenuating secretion and causing lysosomal accumulation of cargo, and its C-terminal region is required to restore proper sorting (PMID:34023780). VPS52 also binds GTP-loaded Arf6 specifically, localizing to the TGN and vesicular endomembranes in hippocampal neurons, where the Arf6 interaction mediates control of dendritic length (PMID:32473257). Its participation in tethering complexes is regulated by the E3 ubiquitin ligase RNF41, which interacts with VPS52 through coiled-coil domains, ubiquitinates it, and redistributes it away from the shared subunit VPS53 (PMID:28542518). Beyond trafficking, VPS52 is required in extraembryonic tissues for pluripotent epiblast differentiation into embryonic ectoderm via cell-cell interactions (PMID:23142660), and its overexpression activates the cathepsin D/Bax/cytochrome C/caspase 9/caspase 3 apoptotic pathway in gastric cancer cells (PMID:28791438).

1. 2003 High

   Established VPS52 as a structural subunit of the GARP tethering complex and defined how that complex bridges to the fusion machinery, answering how endosome-to-TGN retrograde cargo is captured at the Golgi.

   Evidence Genetic analysis, co-immunoprecipitation, and yeast mutant phenotyping of the Vps51/52/53/54 complex

   PMID:12686613

   Open questions at the time

   • No structural model of how VPS52 contributes to the tetramer architecture
   • Did not define mammalian cargo specificity
   • EARP complex membership not addressed in this study
2. 2012 Medium

   Connected VPS52 trafficking function to a developmental requirement, showing that retrograde transport in extraembryonic tissues is needed for epiblast differentiation before gastrulation.

   Evidence Positional cloning of the t(w5) mutation and loss-of-function mouse embryological analysis

   PMID:23142660

   Open questions at the time

   • Molecular cargo whose mistrafficking drives the phenotype not identified
   • No biochemical reconstitution linking trafficking defect to differentiation
   • Mechanism of cell-cell interaction failure unresolved
3. 2017 Medium

   Identified a post-translational regulator of GARP/EARP assembly, showing RNF41 ubiquitinates VPS52 and removes it from the shared VPS53 subunit.

   Evidence Array MAPPIT interaction screen, co-immunoprecipitation, coiled-coil domain mapping, and ubiquitination assay

   PMID:28542518

   Open questions at the time

   • Functional consequence of ubiquitination for trafficking flux not measured
   • Ubiquitin chain type and target lysines not defined
   • Single lab, no in vivo validation
4. 2017 Medium

   Revealed a trafficking-adjacent role in apoptosis, showing VPS52 overexpression engages the cathepsin D mitochondrial apoptotic cascade in gastric cancer.

   Evidence Overexpression in gastric cancer cell lines, xenograft model, and western blot pathway analysis with viability/apoptosis assays

   PMID:28791438

   Open questions at the time

   • Mechanistic link between trafficking function and cathepsin D activation unclear
   • Gain-of-function only; endogenous loss-of-function effect on apoptosis untested
   • Direct molecular target of VPS52 in the pathway not identified
5. 2020 Medium

   Defined a small-GTPase partner and a neuronal function, showing VPS52 binds GTP-Arf6 specifically and uses that interaction to regulate dendritic length.

   Evidence Yeast two-hybrid screening, shRNA knockdown with wild-type and Arf6-binding mutant rescue, and neurite length quantification in hippocampal neurons

   PMID:32473257

   Open questions at the time

   • Whether Arf6 binding occurs within the GARP/EARP context unknown
   • Axonal regulation appears Arf6-independent and mechanistically unexplained
   • No structural definition of the Arf6-binding interface
6. 2021 Medium

   Placed VPS52/GARP downstream of Rab6 in secretory trafficking, showing VPS52 acts as a Rab6 effector whose loss phenocopies Rab6 knockout.

   Evidence CRISPR/Cas9 knockout cell lines, secretion and lysosomal accumulation assays, and C-terminal domain rescue

   PMID:34023780

   Open questions at the time

   • Direct Rab6-VPS52 binding interface not mapped
   • How the same subunit serves both Rab6 and Arf6 functions unresolved
   • Single lab, mammalian cell lines only
7. 2025 Low

   Implicated VPS52 as a host target during plant-aphid interaction, showing it is recruited into a trimeric complex with aphid effectors at vesicular compartments.

   Evidence Co-immunoprecipitation, in vitro recombinant interaction, and confocal microscopy (preprint)

   PMID:bio_10.1101_2025.05.12.653458

   Open questions at the time

   • Preprint; no functional mutagenesis of VPS52 itself
   • Consequence of effector binding for host trafficking unknown
   • Relevance to mammalian VPS52 biology unclear

• How a single VPS52 subunit integrates Rab6- and Arf6-dependent inputs, GARP versus EARP assembly, and RNF41 ubiquitination into coordinated trafficking decisions remains unresolved.
• No structural model of mammalian GARP/EARP with VPS52
• Regulatory logic coupling ubiquitination to complex assembly undefined
• Cargo repertoire and tissue-specific functions incompletely mapped