Affinage

VPS52

Vacuolar protein sorting-associated protein 52 homolog · UniProt Q8N1B4

Round 2 corrected
Length
723 aa
Mass
82.2 kDa
Annotated
2026-04-28
44 papers in source corpus 9 papers cited in narrative 9 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

VPS52 is a core subunit of the GARP (Golgi-Associated Retrograde Protein) tethering complex that orchestrates retrograde vesicle transport from endosomes to the trans-Golgi network and supports anterograde secretory trafficking. Within the tetrameric GARP complex (VPS51/52/53/54), VPS52 directly binds the small GTPase Rab6 and, through VPS51, connects to TGN-resident SNAREs (Tlg1p in yeast; Syntaxin 10, Syntaxin 6, Syntaxin 16, and VAMP4 in mammals), coupling vesicle tethering to SNARE complex assembly for membrane fusion (PMID:12686613, PMID:15878329, PMID:19620288). Loss of VPS52 impairs retrograde delivery of mannose 6-phosphate receptors and cathepsin D to lysosomes, blocks Shiga toxin and TGN46 recycling, and attenuates Rab6-dependent secretory cargo export (PMID:18367545, PMID:34023780). In mice, Vps52 loss-of-function (the t(w5) lethal allele) causes embryonic lethality with defective extraembryonic tissue differentiation, and in neurons VPS52 interacts with GTP-Arf6 to negatively regulate dendritic outgrowth (PMID:23142660, PMID:32473257).

Mechanistic history

Synthesis pass · year-by-year structured walk · 8 steps
  1. 2003 High

    Identification of Vps52 as a subunit of the tetrameric GARP/VFT complex established the molecular composition of the tethering machinery for endosome-to-TGN retrograde transport and revealed that the fourth subunit Vps51 bridges the complex to the t-SNARE Tlg1p.

    Evidence Genetic complementation, co-immunoprecipitation, and yeast two-hybrid assays in S. cerevisiae

    PMID:12686613

    Open questions at the time
    • Mammalian GARP composition and cognate SNAREs not yet defined
    • Direct tethering activity of the GARP complex not demonstrated in vitro
  2. 2005 High

    Demonstration that human VPS52 binds Rab6 and associates with Syntaxin 10 extended the GARP tethering model to mammals, identifying the GTPase receptor and the species-specific SNARE partner at the TGN.

    Evidence Subcellular fractionation, immunofluorescence, and co-immunoprecipitation in human cells

    PMID:15878329

    Open questions at the time
    • Structural basis of VPS52–Rab6 interaction unknown
    • Whether VPS52 or another GARP subunit directly contacts Syntaxin 10 not resolved
  3. 2008 High

    Functional depletion studies proved GARP/VPS52 is required for retrograde trafficking of multiple cargos—mannose 6-phosphate receptors, TGN46, and Shiga toxin—establishing the complex as a general retrograde tethering factor rather than pathway-specific.

    Evidence RNAi knockdown with cathepsin D secretion, Shiga toxin transport, and TGN46 localization assays in mammalian cells

    PMID:18367545

    Open questions at the time
    • Relative contribution of individual GARP subunits to cargo selectivity not dissected
    • Whether GARP also participates in anterograde pathways not addressed
  4. 2009 High

    Reconstitution of GARP tethering activity in vitro and mapping of SNARE interactions to VPS53/VPS54 N-termini demonstrated that GARP performs two separable functions—vesicle tethering and SNARE complex assembly—as consecutive steps in retrograde transport.

    Evidence In vitro tethering assay, co-immunoprecipitation, and deletion mutagenesis

    PMID:19620288

    Open questions at the time
    • Direct structural model of GARP–SNARE interaction lacking
    • Specific role of VPS52 within the tethering versus SNARE-assembly steps not separated
  5. 2012 High

    Positional cloning of the mouse t(w5) lethal as a Vps52 loss-of-function allele revealed that GARP-mediated trafficking is essential for embryonic development, particularly extraembryonic tissue differentiation and ectodermal patterning.

    Evidence Positional cloning, genetic complementation, and embryo phenotyping in mutant mice

    PMID:23142660

    Open questions at the time
    • Which specific trafficking cargos underlie the developmental defect is unknown
    • Whether GARP complex integrity is completely lost or partially retained in the mutant not determined
  6. 2017 Medium

    Discovery that RNF41 ubiquitinates VPS52 via coiled-coil domain interaction and displaces it from VPS53 provided the first post-translational regulatory mechanism controlling GARP/EARP complex assembly.

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

    PMID:28542518

    Open questions at the time
    • Ubiquitination site(s) on VPS52 not mapped
    • Functional consequence for endosome-to-TGN transport not tested
    • Not independently confirmed by a second group
  7. 2020 Medium

    Identification of VPS52 as an Arf6-GTP effector in neurons, where the Arf6-binding region selectively regulates dendritic but not axonal outgrowth, expanded VPS52 function beyond canonical GARP tethering to neuronal morphogenesis.

    Evidence Yeast two-hybrid screen, shRNA knockdown, and domain-mutant rescue in hippocampal neurons

    PMID:32473257

    Open questions at the time
    • Whether Arf6–VPS52 interaction operates through the GARP complex or independently is unresolved
    • Downstream effectors mediating dendritic outgrowth regulation not identified
  8. 2021 Medium

    CRISPR knockout of VPS52 phenocopied Rab6 loss for secretory cargo export and lysosomal sorting, establishing VPS52/GARP as a Rab6 effector in the anterograde secretory pathway and assigning a functional role to the previously uncharacterized VPS52 C-terminal domain.

    Evidence CRISPR knockout, secretory and lysosomal sorting assays, C-terminal deletion rescue in human cells

    PMID:34023780

    Open questions at the time
    • Structural basis of the C-terminal domain's contribution unknown
    • Whether VPS52 KO secretory defect is solely GARP-dependent or also involves EARP not tested

Open questions

Synthesis pass · forward-looking unresolved questions
  • No high-resolution structure of VPS52 within the GARP complex exists, and the mechanistic basis by which VPS52 simultaneously coordinates Rab6, Arf6, and SNARE interactions across different cellular contexts remains unresolved.
  • No atomic-resolution structure of VPS52 or GARP complex available
  • How RNF41-mediated ubiquitination modulates GARP versus EARP partitioning in vivo is untested
  • Physiological relevance of VPS52 tumor-suppressive activity in gastric cancer requires genetic validation

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060090 molecular adaptor activity 3
Localization
GO:0005768 endosome 2 GO:0005794 Golgi apparatus 2 GO:0031410 cytoplasmic vesicle 2
Pathway
R-HSA-5653656 Vesicle-mediated transport 5 R-HSA-9612973 Autophagy 2 R-HSA-392499 Metabolism of proteins 1
Partners
ARF6RAB6ASTX10STX16STX6VPS51VPS53VPS54
Complex memberships
EARP complexGARP complex (VPS51/VPS52/VPS53/VPS54)

Evidence

Reading pass · 9 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2003 Vps52 is a core subunit of the tetrameric GARP (Golgi-Associated Retrograde Protein) complex (Vps51/52/53/54). The additional subunit Vps51p mediates the interaction between the Vps52/53/54 sub-complex and the late Golgi t-SNARE Tlg1p via binding to the conserved N-terminal domain of Tlg1p, providing a crucial link between tethering and fusion machinery. All four subunits are required for retrograde transport from both early and late endosomes back to the TGN. Genetic complementation, co-immunoprecipitation, two-hybrid interaction assays in yeast Molecular biology of the cell High 12686613
2005 Human VPS52 (hVps52) is a subunit of the human GARP/VFT tethering complex and localizes to smooth membrane/Golgi fractions and perinuclear vesicular structures with endosomal character near the TGN. hVps52 specifically binds the small GTPase Rab6 (human homolog of yeast Ypt6p). In human cells, hVps52 mediates binding of the GARP complex to the orphan SNARE Syntaxin 10, revealing Syntaxin 10 as the human-specific GARP-associated SNARE for membrane docking and fusion at the Golgi. Subcellular fractionation, immunostaining with endosomal markers, co-immunoprecipitation Experimental cell research High 15878329
2008 Depletion of VPS52 (along with VPS53 or VPS54) by RNAi impairs mannose 6-phosphate receptor (MPR)-dependent sorting of cathepsin D precursor to lysosomes, causing cathepsin D secretion into the medium, lysosomal swelling, and accumulation of recycling MPRs in light vesicles downstream of endosomes. GARP/VPS52 also blocks retrograde transport of TGN46 and the B subunit of Shiga toxin, establishing a general role for the GARP complex in retrograde cargo delivery to the TGN. RNAi knockdown in mammalian cells, cathepsin D trafficking assay, Shiga toxin transport assay, TGN46 localization Molecular biology of the cell High 18367545
2009 The mammalian GARP complex interacts specifically with SNAREs syntaxin 6, syntaxin 16, and Vamp4 (participants in endosome-to-TGN transport) via the N-terminal regions of VPS53 and VPS54 and the SNARE motifs of the SNAREs. GARP functions upstream of SNAREs, regulating their localization and assembly into SNARE complexes. In vitro data support a tethering role for GARP. These two functions — tethering and SNARE complex assembly — are consecutive, independent steps in retrograde transport. Co-immunoprecipitation, RNAi depletion, in vitro tethering assay, deletion mutagenesis of VPS53 Molecular and cellular biology High 19620288
2012 The mouse t(w5) lethal mutation is caused by a loss-of-function mutation in Vps52. Vps52 acts in extraembryonic tissues to support growth and differentiation of the embryonic ectoderm via cell-cell interactions, and is also required for formation of embryonic structures at later developmental stages, revealing functions in multicellular development beyond its known role in endosomal retrograde trafficking. Positional cloning, genetic complementation, embryo phenotyping in Vps52 mutant mice Cell reports High 23142660
2017 RNF41, an E3 ubiquitin ligase, interacts with VPS52 through their coiled-coil domains. RNF41 ubiquitinates VPS52 and relocates it away from VPS53 (a common subunit of GARP and EARP complexes) toward RNF41 bodies, indicating that RNF41-mediated ubiquitination regulates VPS52's association with the GARP and EARP complexes. Array MAPPIT protein-protein interaction screen, co-immunoprecipitation, coiled-coil domain interaction mapping, ubiquitination assay PloS one Medium 28542518
2017 Overexpression of VPS52 in gastric cancer cells activates the cathepsin D/Bax/cytochrome C/caspase 9/caspase 3 apoptotic pathway, reducing cell viability and inducing apoptosis in vitro, and reducing tumor volume in xenograft models in vivo. This identifies VPS52 as a tumor suppressor in gastric cancer that promotes apoptosis through cathepsin D activation. VPS52 overexpression in gastric cancer cell lines, cell viability assay, apoptosis assay, Western blot for apoptotic pathway components, xenograft mouse model Journal of molecular medicine Medium 28791438
2020 VPS52 is a novel Arf6-binding protein identified by yeast two-hybrid screening. VPS52 interacts specifically with GTP-bound Arf6 (active form) among the Arf family. In hippocampal neurons, VPS52 localizes to the trans-Golgi network and vesicular endomembranes in cell bodies and dendritic shafts. Knockdown of Vps52 increases total axon and dendrite length; this phenotype is rescued by full-length Vps52 but only partially by a mutant lacking Arf6-binding ability, indicating that the Arf6 interaction specifically regulates dendritic (but not axonal) outgrowth. Yeast two-hybrid screening, immunohistochemistry, shRNA knockdown, rescue with mutant constructs in hippocampal neurons Brain research Medium 32473257
2021 VPS52 functions as a Rab6 effector responsible for Rab6-dependent secretory cargo trafficking. Knockout of VPS52 in human cells results in attenuated secretion and lysosomal accumulation of secretory cargos, phenocopying Rab6 knockout. The previously uncharacterized C-terminal region of VPS52 is functionally important for restoring secretory cargo trafficking and for lysosomal protein sorting. CRISPR knockout cell lines, secretory cargo trafficking assays, lysosomal protein sorting assay, C-terminal deletion rescue experiments Biochemical and biophysical research communications Medium 34023780

Source papers

Stage 0 corpus · 44 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2002 Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences. Proceedings of the National Academy of Sciences of the United States of America 1479 12477932
2015 The BioPlex Network: A Systematic Exploration of the Human Interactome. Cell 1118 26186194
2017 Architecture of the human interactome defines protein communities and disease networks. Nature 1085 28514442
2015 A human interactome in three quantitative dimensions organized by stoichiometries and abundances. Cell 1015 26496610
2014 A proteome-scale map of the human interactome network. Cell 977 25416956
2020 A reference map of the human binary protein interactome. Nature 849 32296183
2003 Complete sequencing and characterization of 21,243 full-length human cDNAs. Nature genetics 754 14702039
2021 Dual proteome-scale networks reveal cell-specific remodeling of the human interactome. Cell 705 33961781
2012 A census of human soluble protein complexes. Cell 689 22939629
2015 Gene essentiality and synthetic lethality in haploid human cells. Science (New York, N.Y.) 657 26472760
2011 Phylogenetic-based propagation of functional annotations within the Gene Ontology consortium. Briefings in bioinformatics 656 21873635
1994 Oligo-capping: a simple method to replace the cap structure of eukaryotic mRNAs with oligoribonucleotides. Gene 492 8125298
2004 The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC). Genome research 438 15489334
2016 Widespread Expansion of Protein Interaction Capabilities by Alternative Splicing. Cell 423 26871637
2021 A proximity-dependent biotinylation map of a human cell. Nature 339 34079125
2008 Hepatitis C virus infection protein network. Molecular systems biology 306 18985028
2016 The cell proliferation antigen Ki-67 organises heterochromatin. eLife 265 26949251
2003 The DNA sequence and analysis of human chromosome 6. Nature 242 14574404
2011 Next-generation sequencing to generate interactome datasets. Nature methods 200 21516116
2015 A deep proteomics perspective on CRM1-mediated nuclear export and nucleocytoplasmic partitioning. eLife 198 26673895
2014 Global mapping of herpesvirus-host protein complexes reveals a transcription strategy for late genes. Molecular cell 173 25544563
2003 Vps51p mediates the association of the GARP (Vps52/53/54) complex with the late Golgi t-SNARE Tlg1p. Molecular biology of the cell 151 12686613
2018 Discovery and Characterization of ZUFSP/ZUP1, a Distinct Deubiquitinase Class Important for Genome Stability. Molecular cell 150 29576527
2020 A High-Density Human Mitochondrial Proximity Interaction Network. Cell metabolism 148 32877691
2019 Mapping the proximity interaction network of the Rho-family GTPases reveals signalling pathways and regulatory mechanisms. Nature cell biology 137 31871319
2008 Requirement of the human GARP complex for mannose 6-phosphate-receptor-dependent sorting of cathepsin D to lysosomes. Molecular biology of the cell 133 18367545
2009 Dual roles of the mammalian GARP complex in tethering and SNARE complex assembly at the trans-golgi network. Molecular and cellular biology 120 19620288
2017 The human cytoplasmic dynein interactome reveals novel activators of motility. eLife 118 28718761
2014 Protein interaction network of alternatively spliced isoforms from brain links genetic risk factors for autism. Nature communications 111 24722188
2019 Systematic bromodomain protein screens identify homologous recombination and R-loop suppression pathways involved in genome integrity. Genes & development 110 31753913
2005 Characterization of the human GARP (Golgi associated retrograde protein) complex. Experimental cell research 109 15878329
2018 Genetic variations in ARE1 mediate grain yield by modulating nitrogen utilization in rice. Nature communications 95 29467406
2017 An Aphid Effector Targets Trafficking Protein VPS52 in a Host-Specific Manner to Promote Virulence. Plant physiology 79 28100451
2002 Linkage between polymorphisms in the prostate specific antigen ARE1 gene region, prostate cancer risk, and circulating tumor cells. The Prostate 55 12210484
2021 Increasing yield potential through manipulating of an ARE1 ortholog related to nitrogen use efficiency in wheat by CRISPR/Cas9. Journal of integrative plant biology 53 34270164
2021 The Ghd7 transcription factor represses ARE1 expression to enhance nitrogen utilization and grain yield in rice. Molecular plant 52 33930508
2012 Molecular identification of t(w5): Vps52 promotes pluripotential cell differentiation through cell-cell interactions. Cell reports 28 23142660
2019 The GATA-Type Transcriptional Factor Are1 Modulates the Expression of Extracellular Proteases and Cellulases in Trichoderma reesei. International journal of molecular sciences 25 31443450
2013 Phosphatidic acid and phosphoinositides facilitate liposome association of Yas3p and potentiate derepression of ARE1 (alkane-responsive element one)-mediated transcription control. Fungal genetics and biology : FG & B 19 24120453
2017 VPS52 induces apoptosis via cathepsin D in gastric cancer. Journal of molecular medicine (Berlin, Germany) 14 28791438
2017 RNF41 interacts with the VPS52 subunit of the GARP and EARP complexes. PloS one 13 28542518
2020 The Vps52 subunit of the GARP and EARP complexes is a novel Arf6-interacting protein that negatively regulates neurite outgrowth of hippocampal neurons. Brain research 10 32473257
2021 Knockout analysis of Rab6 effector proteins revealed the role of VPS52 in the secretory pathway. Biochemical and biophysical research communications 9 34023780
2024 Are1-mediated nitrogen metabolism is associated with iron regulation in the mycoparasite Trichoderma atroviride. Microbiological research 2 39348793