Affinage

VPS18

Vacuolar protein sorting-associated protein 18 homolog · UniProt Q9P253

Round 2 corrected
Length
973 aa
Mass
110.2 kDa
Annotated
2026-04-28
53 papers in source corpus 16 papers cited in narrative 16 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

VPS18 is a scaffold subunit shared by the HOPS and CORVET membrane-tethering complexes that orchestrates multiple vesicular trafficking routes to lysosomes, including endocytic, autophagic, phagocytic, and biosynthetic pathways. Its C-terminal RING domain forms a metazoan-specific heterodimer with the VPS41 RING domain to recruit VPS41 into the HOPS complex, and VPS18 also functions as an E3 ubiquitin ligase that modulates Wnt, ERα/PELP1, and NF-κB signaling (PMID:28931724, PMID:31015428). Loss of VPS18 blocks lysosomal degradation of cargo such as EGFR and Lysyl Oxidase, leading to neurodegeneration, impaired dendritogenesis, and enhanced EGFR-ERK signaling in tumorigenesis, and it compromises phagosomal membrane integrity during Mycobacterium tuberculosis infection (PMID:22854957, PMID:40615043, PMID:39888996). Heterozygous VPS18 loss-of-function mutations cause neutropenia through CORVET/HOPS complex instability, impaired vesicle dynamics, and premature neutrophil progenitor apoptosis (PMID:41526335).

Mechanistic history

Synthesis pass · year-by-year structured walk · 12 steps
  1. 1991 High

    Identification of PEP3/VPS18 as a gene required for vacuolar biogenesis in yeast established that the protein is essential for vesicular delivery of hydrolases to the vacuole, founding the class C VPS pathway.

    Evidence Complementation cloning, gene disruption, subcellular fractionation, and electron microscopy in S. cerevisiae

    PMID:1944264

    Open questions at the time
    • Mammalian ortholog not yet cloned
    • No complex membership determined
    • Biochemical activity unknown
  2. 2001 Medium

    Cloning of human VPS18 and the three other class C VPS genes confirmed evolutionary conservation from yeast to mammals and implicated the pathway in human lysosomal protein delivery.

    Evidence Molecular cloning and sequence/expression analysis

    PMID:11250079

    Open questions at the time
    • No functional data in mammalian cells
    • Complex assembly not tested
    • No disease association
  3. 2005 High

    Zebrafish vps18 mutants revealed that VPS18 is required in vertebrates for endosomal-lysosomal trafficking and apical membrane biogenesis in hepatocytes, extending the role beyond generic vacuolar sorting to organ-specific vesicular pathways.

    Evidence Insertional mutagenesis screen with histology, EM, and live imaging in zebrafish

    PMID:16000385

    Open questions at the time
    • Mechanism of apical membrane sorting unclear
    • HOPS versus CORVET contribution not distinguished
  4. 2006 Medium

    Demonstration that zebrafish vps18 mutation blocks melanosome maturation established VPS18-dependent trafficking as essential for lysosome-related organelle biogenesis.

    Evidence Insertional mutagenesis with histology and optokinetic response assay in zebrafish larvae

    PMID:16827750

    Open questions at the time
    • Direct HOPS complex involvement inferred but not biochemically tested
    • Mammalian melanosome phenotype not examined
  5. 2008 High

    Two parallel studies showed VPS18 functions in phagosome-lysosome fusion (C. elegans) and autophagosome-lysosome fusion via interaction with UVRAG-Beclin1 and Rab7 activation (mammalian cells), establishing VPS18 as a convergence point for degradative vesicle fusion pathways.

    Evidence VPS-18 deletion mutant analysis with phagosome-lysosome fusion assays in C. elegans; Co-IP and Rab7 GTPase activity assays with autophagic flux measurement in mammalian cells

    PMID:18552835 PMID:18923146

    Open questions at the time
    • Structural basis of Rab7 activation not resolved
    • Whether VPS18 directly contacts UVRAG or acts through other class C subunits unclear
  6. 2012 High

    Conditional knockout of Vps18 in mouse neurons revealed that VPS18 is essential for lysosomal homeostasis in the CNS: its loss blocks autophagy, endocytosis, and biosynthetic trafficking, causing neurodegeneration, β1 integrin accumulation, and Lysyl Oxidase-dependent dendrite defects.

    Evidence Nestin-Cre conditional KO mice with autophagy/endocytosis flux assays, Western blot, siRNA rescue; Purkinje cell-specific KO with Lox accumulation analysis

    PMID:22699122 PMID:22854957

    Open questions at the time
    • Whether Lox is a direct VPS18 substrate or passively stabilized by lysosomal failure not distinguished
    • Relative HOPS versus CORVET contribution to dendritogenesis unknown
  7. 2014 High

    Identification of STX17 as the autophagosomal SNARE that directly recruits HOPS (including VPS18) resolved how autophagosomes are targeted for lysosomal fusion.

    Evidence Reciprocal Co-IP, mass spectrometry, siRNA knockdown with autophagic flux assays in mammalian cells

    PMID:24554770

    Open questions at the time
    • Structural details of HOPS-STX17 interface lacking
    • Whether VPS18 directly contacts STX17 not determined
  8. 2017 High

    Biochemical demonstration that the VPS18 C-terminal RING domain directly heterodimerizes with VPS41 RING domain established the metazoan-specific mechanism by which VPS41 is recruited into the HOPS complex.

    Evidence Biochemical pulldown, Co-IP with endogenous HOPS, domain truncation/mutant analysis

    PMID:28931724

    Open questions at the time
    • High-resolution structure of the RING-RING heterodimer not available
    • Whether this interaction is regulated remains unknown
  9. 2019 High

    Discovery that VPS18 (and VPS11) possess RING-dependent E3 ubiquitin ligase activity with PELP1 as a substrate added a catalytic signaling function to VPS18 beyond its tethering role, linking it to Wnt, ERα, and NF-κB pathway modulation.

    Evidence In vitro E3 ligase and ubiquitination assays, Co-IP, overexpression in Drosophila and mammalian cells with signaling readouts

    PMID:31015428

    Open questions at the time
    • Full substrate repertoire unknown
    • Physiological relevance of E3 activity versus tethering function not genetically separated
  10. 2024 Medium

    VPS18 was shown to interact with PD-L1 in endosomal recycling compartments, promoting its glycosylation and surface stability; VPS18 depletion reduced PD-L1 levels and enhanced antitumor immunity, revealing an immuno-oncology axis through endosomal trafficking.

    Evidence Co-IP, CRISPR/siRNA knockdown, PD-L1 stability and glycosylation assays, in vivo tumor models

    PMID:39413192

    Open questions at the time
    • Direct versus indirect mechanism of PD-L1 glycosylation enhancement not resolved
    • Whether VPS18 E3 ligase activity participates in PD-L1 regulation untested
  11. 2025 High

    Genome-wide CRISPR screen and validation identified VPS18 as essential for phagosomal membrane integrity during M. tuberculosis infection; separately, VPS18 loss elevated EGFR protein and ERK signaling in K-Ras-driven lung tumors, establishing a VPS18-EGFR-ERK degradative axis in tumorigenesis.

    Evidence CRISPR screen and KO with galectin damage assays in macrophages; conditional KO in LSL-K-Ras mice with dominant-negative EGFR rescue

    PMID:39888996 PMID:40615043

    Open questions at the time
    • Whether VPS18 acts at phagosomal membranes independently of full HOPS complex not tested
    • Mechanism of phagosomal membrane stabilization unknown
  12. 2026 High

    Heterozygous VPS18 stop-gain mutations were identified as a cause of neutropenia in humans, with VPS18 deficiency destabilizing CORVET/HOPS, blocking vesicle dynamics and causing autophagosome accumulation and premature apoptosis in neutrophil progenitors — the first Mendelian disease link for VPS18.

    Evidence Patient mutation, CRISPR/Cas9 in Hoxb8 cells, iPSC differentiation, TEM, LC3/p62 Western blot, zebrafish model

    PMID:41526335

    Open questions at the time
    • Genotype-phenotype spectrum beyond neutropenia not defined
    • Whether homozygous loss is embryonic lethal in humans unknown
    • Therapeutic rescue strategies not explored

Open questions

Synthesis pass · forward-looking unresolved questions
  • A high-resolution structure of the full human HOPS or CORVET complex with VPS18 is lacking, and the physiological balance between VPS18's tethering/scaffolding role and its E3 ubiquitin ligase activity has not been genetically dissected in vivo.
  • No cryo-EM or crystal structure of human HOPS/CORVET complex
  • E3 ligase versus scaffolding function not genetically separated
  • Full substrate repertoire of VPS18 E3 activity undefined

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0005198 structural molecule activity 3 GO:0016874 ligase activity 1 GO:0140096 catalytic activity, acting on a protein 1
Localization
GO:0005764 lysosome 5 GO:0005768 endosome 3 GO:0031410 cytoplasmic vesicle 3
Pathway
R-HSA-5653656 Vesicle-mediated transport 8 R-HSA-9612973 Autophagy 4 R-HSA-1852241 Organelle biogenesis and maintenance 3 R-HSA-162582 Signal Transduction 2 R-HSA-168256 Immune System 2
Partners
PELP1STX17UVRAGVPS11VPS16VPS33AVPS41
Complex memberships
CORVET complexHOPS complex

Evidence

Reading pass · 16 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1991 Yeast PEP3/VPS18 encodes a 107-kDa hydrophilic vacuolar peripheral membrane protein required for vacuolar biogenesis; loss-of-function results in accumulation of small vesicles instead of normal vacuoles and defects in delivery of vacuolar hydrolases (protease A, protease B, carboxypeptidase Y). Complementation cloning, deletion/disruption alleles, subcellular fractionation of PEP3::SUC2 fusion, fluorescence and electron microscopy Molecular and cellular biology High 1944264
2001 Human VPS18 (and VPS11, VPS16, VPS33) are homologs of yeast class C VPS genes; the four proteins are expressed in human tissues and are candidates for involvement in lysosomal protein delivery pathways conserved from yeast to mammals. Molecular cloning, sequence analysis, expression pattern determination Gene Medium 11250079
2005 Zebrafish vps18 mutation (class C VPS gene) causes hepatomegaly with vesicle-filled hepatocytes attributable to failure of endosomal-lysosomal trafficking, defects in bile canaliculi, and biliary paucity, demonstrating that vps18 is required for vesicle trafficking to both the lysosomal and hepatocyte apical membrane compartments. Insertional mutagenesis screen, histology, electron microscopy, live imaging in zebrafish embryos Development (Cambridge, England) High 16000385
2006 Zebrafish vps18 mutant (retroviral insertion in exon 4 disrupting clathrin repeat and RING finger domains) shows severe reduction in melanosomes in retinal pigmented epithelium with accumulation of immature melanosomes, establishing that Vps18 is required for melanosome biogenesis via its role in the HOPS complex during vesicular traffic. Insertional mutagenesis, RT-PCR of splicing variants, histology, optokinetic response assay in zebrafish larvae Pigment cell research Medium 16827750
2008 C. elegans VPS-18 functions in engulfing cells to mediate lysosome biogenesis and phagosome-lysosome fusion; vps-18 deletion causes accumulation of undegraded apoptotic cell corpses due to failure of phagosome fusion with lysosomes. Deletion mutant analysis, fluorescence microscopy of endosomal/lysosomal markers, phagosome-lysosome fusion assay in C. elegans Molecular biology of the cell High 18923146
2008 The class C Vps complex (including Vps18) interacts with UVRAG-Beclin1 to stimulate Rab7 GTPase activity and promote autophagosome fusion with late endosomes/lysosomes as well as endosome-endosome fusion. Co-immunoprecipitation, Rab7 GTPase activity assay, autophagic flux assays in mammalian cells Nature cell biology High 18552835
2011 Human Vps18 and its yeast ortholog are required for efficient HIV-1 Gag-induced viruslike particle release and infectious virion production; depletion of hVps18 in human cells reduces infectious HIV-1 particle yield, placing Vps18-dependent trafficking in the HIV-1 budding pathway. Yeast genetic screen, siRNA knockdown in human cells, VLP release assay, viral infectivity measurement Journal of virology Medium 21450827
2012 Conditional knockout of Vps18 in neural cells (Nestin-Cre) causes neurodegeneration by blocking multiple vesicle transport pathways to the lysosome including autophagy, endocytosis, and biosynthetic pathways; Vps18 deficiency also causes β1 integrin upregulation due to lysosomal dysfunction, contributing to neuronal migration defects that are partially rescued by β1 integrin knockdown. Conditional KO mice (Vps18-F/F; Nestin-Cre), immunohistochemistry, Western blot, autophagy/endocytosis flux assays, siRNA rescue experiments The Journal of biological chemistry High 22854957
2012 Vps18 deficiency in Purkinje cells blocks dendrite development by preventing lysosomal degradation of Lysyl Oxidase (Lox); Lox protein accumulates in Vps18-deficient cerebellum, linking lysosomal degradative function to dendritogenesis. Conditional KO mice, immunohistochemistry, Western blot for Lox in cerebellum vs. cortex Biochemical and biophysical research communications Medium 22699122
2014 The HOPS complex (including VPS18) interacts with autophagosomal SNARE syntaxin 17 (STX17) to promote autophagosome-lysosome fusion; knockdown of HOPS subunits blocks autophagic flux and causes accumulation of STX17/LC3-positive autophagosomes. Immunoprecipitation, mass spectrometry, siRNA knockdown, autophagic flux assays in mammalian cells Molecular biology of the cell High 24554770
2017 Human VPS18 RING domain directly interacts with the RING domain of VPS41 to form a stable heterodimer required for VPS41 recruitment to the core HOPS complex; this RING-RING interaction is unique to metazoans as yeast Vps41 lacks a C-terminal zinc-finger motif. Biochemical pulldown, co-immunoprecipitation with endogenous HOPS, domain truncation/mutant analysis The Biochemical journal High 28931724
2019 Vps11 and Vps18 (shared HOPS/CORVET subunits) function as E3 ubiquitin ligases; overexpression perturbs ubiquitination in signal transduction pathways including Wnt, ERα, and NFκB; specifically, Vps11/18-mediated ubiquitination of scaffold protein PELP1 impairs ERα activation by c-Src. E3 ligase activity assays, ubiquitination assays, Co-IP, overexpression in Drosophila and mammalian cells, signaling pathway readouts Nature communications High 31015428
2024 VPS11/18 interact with PD-L1 in endosomal recycling and promote PD-L1 glycosylation and protein stability; VPS18 deficiency reduces PD-L1 surface levels and enhances antitumor immune response; VPS18 mediates trans-Golgi network recycling of PD-L1. Co-immunoprecipitation, siRNA/CRISPR knockdown, PD-L1 stability and glycosylation assays, in vivo tumor models, pharmacological inhibition Science advances Medium 39413192
2025 VPS18 is required for phagosomal membrane integrity in Mycobacterium tuberculosis-infected macrophages; VPS18-knockout macrophages show increased phagosomal damage without impaired autophagy, Mtb grows more robustly, and antibiotic efficacy (pyrazinamide) is reduced; VPS18 colocalizes with Mtb-containing phagosomes shortly after infection. Genome-wide CRISPR screen, CRISPR KO, galectin-based phagosomal damage assay, live-cell imaging, antibiotic efficacy assay Science advances High 39888996
2025 Vps18 deficiency in LSL-K-Ras lung tumors elevates EGFR protein levels and activates ERK-MAPK signaling; expression of dominant-negative EGFR partially suppresses the tumor-promoting effects of Vps18 loss, establishing a Vps18-EGFR-ERK axis in lung tumorigenesis via lysosomal degradation of EGFR. Conditional KO in LSL-K-Ras mice, Western blot, EGFR dominant-negative rescue, ERK-MAPK pathway analysis The Journal of biological chemistry Medium 40615043
2026 VPS18 deficiency in neutrophil progenitors causes CORVET/HOPS tethering complex instability, impaired vesicle dynamics with autophagosome accumulation (increased LC3B-II and p62), and premature apoptosis, resulting in a neutrophil maturation defect; heterozygous VPS18 stop-gain mutations in a human patient and in iPSC/zebrafish models cause neutropenia. CRISPR/Cas9 Hoxb8 cells, iPSC differentiation, TEM, LC3/p62 Western blot, zebrafish model, patient mutation characterization Cell death & disease High 41526335

Source papers

Stage 0 corpus · 53 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2006 Global, in vivo, and site-specific phosphorylation dynamics in signaling networks. Cell 2861 17081983
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
2010 Network organization of the human autophagy system. Nature 1286 20562859
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
2018 VIRMA mediates preferential m6A mRNA methylation in 3'UTR and near stop codon and associates with alternative polyadenylation. Cell discovery 829 29507755
2007 Large-scale mapping of human protein-protein interactions by mass spectrometry. Molecular systems biology 733 17353931
2012 Quantitative analysis of HSP90-client interactions reveals principles of substrate recognition. Cell 708 22939624
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
2011 Phylogenetic-based propagation of functional annotations within the Gene Ontology consortium. Briefings in bioinformatics 656 21873635
2008 Beclin1-binding UVRAG targets the class C Vps complex to coordinate autophagosome maturation and endocytic trafficking. Nature cell biology 629 18552835
2010 Identification of the switch in early-to-late endosome transition. Cell 582 20434987
2021 Multilevel proteomics reveals host perturbations by SARS-CoV-2 and SARS-CoV. Nature 532 33845483
2004 The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC). Genome research 438 15489334
2022 OpenCell: Endogenous tagging for the cartography of human cellular organization. Science (New York, N.Y.) 432 35271311
2015 Panorama of ancient metazoan macromolecular complexes. Nature 407 26344197
2014 The HOPS complex mediates autophagosome-lysosome fusion through interaction with syntaxin 17. Molecular biology of the cell 404 24554770
2021 A proximity-dependent biotinylation map of a human cell. Nature 339 34079125
2020 ORF3a of the COVID-19 virus SARS-CoV-2 blocks HOPS complex-mediated assembly of the SNARE complex required for autolysosome formation. Developmental cell 302 33422265
2013 Cellular mechanotransduction relies on tension-induced and chaperone-assisted autophagy. Current biology : CB 243 23434281
2012 Genome-wide association for abdominal subcutaneous and visceral adipose reveals a novel locus for visceral fat in women. PLoS genetics 222 22589738
2014 Proximity biotinylation and affinity purification are complementary approaches for the interactome mapping of chromatin-associated protein complexes. Journal of proteomics 215 25281560
2011 Toward an understanding of the protein interaction network of the human liver. Molecular systems biology 207 21988832
2018 An AP-MS- and BioID-compatible MAC-tag enables comprehensive mapping of protein interactions and subcellular localizations. Nature communications 201 29568061
2011 Protein interactome reveals converging molecular pathways among autism disorders. Science translational medicine 180 21653829
2007 Integral and associated lysosomal membrane proteins. Traffic (Copenhagen, Denmark) 163 17897319
2011 Lysosomal trafficking, antigen presentation, and microbial killing are controlled by the Arf-like GTPase Arl8b. Immunity 156 21802320
2018 Discovery and Characterization of ZUFSP/ZUP1, a Distinct Deubiquitinase Class Important for Genome Stability. Molecular cell 150 29576527
2005 A genetic screen in zebrafish identifies the mutants vps18, nf2 and foie gras as models of liver disease. Development (Cambridge, England) 150 16000385
1991 Isolation and characterization of PEP3, a gene required for vacuolar biogenesis in Saccharomyces cerevisiae. Molecular and cellular biology 64 1944264
2001 Molecular cloning and characterization of human VPS18, VPS 11, VPS16, and VPS33. Gene 59 11250079
2008 Lysosome biogenesis mediated by vps-18 affects apoptotic cell degradation in Caenorhabditis elegans. Molecular biology of the cell 49 18923146
2006 The zebrafish mutant vps18 as a model for vesicle-traffic related hypopigmentation diseases. Pigment cell research 44 16827750
2012 Ablation of vacuole protein sorting 18 (Vps18) gene leads to neurodegeneration and impaired neuronal migration by disrupting multiple vesicle transport pathways to lysosomes. The Journal of biological chemistry 39 22854957
2019 Vps11 and Vps18 of Vps-C membrane traffic complexes are E3 ubiquitin ligases and fine-tune signalling. Nature communications 33 31015428
2023 RALF22 promotes plant immunity and amplifies the Pep3 immune signal. Journal of integrative plant biology 31 37698076
1980 Peptidase-3 (Pep-3), dipeptidase variant in the rat homologous to mouse pep-3 (Dip-1) and human PEP-c. Biochemical genetics 28 7225079
2021 VPS18-regulated vesicle trafficking controls the secretion of pectin and its modifying enzyme during pollen tube growth in Arabidopsis. The Plant cell 23 34125904
2001 Aspergillus nidulans DigA, a potential homolog of Saccharomyces cerevisiae Pep3 (Vps18), is required for nuclear migration, mitochondrial morphology and polarized growth. Molecular genetics and genomics : MGG 22 11810240
2017 VPS18 recruits VPS41 to the human HOPS complex via a RING-RING interaction. The Biochemical journal 21 28931724
2011 The cellular factors Vps18 and Mon2 are required for efficient production of infectious HIV-1 particles. Journal of virology 17 21450827
2020 Circ-VPS18 Knockdown Enhances TMZ Sensitivity and Inhibits Glioma Progression by MiR-370/RUNX1 Axis. Journal of molecular neuroscience : MN 15 33188501
2022 Circular RNA VPS18 Promotes Glioblastoma Progression by Regulating miR-1229-3p/BCAT1 Axis. Neurotoxicity research 13 35776379
2012 Vps18 deficiency inhibits dendritogenesis in Purkinje cells by blocking the lysosomal degradation of Lysyl Oxidase. Biochemical and biophysical research communications 11 22699122
2024 Targeting VPS18 hampers retromer trafficking of PD-L1 and augments immunotherapy. Science advances 10 39413192
2025 VPS18 contributes to phagosome membrane integrity in Mycobacterium tuberculosis-infected macrophages. Science advances 5 39888996
2023 Vps18 contributes to phagosome membrane integrity in Mycobacterium tuberculosis-infected macrophages. bioRxiv : the preprint server for biology 4 37873319
2022 Research on PEP-3 psychological education evaluation system for disabled children and autistic children in minority areas. European review for medical and pharmacological sciences 3 36066153
2025 Vacuole protein sorting 18 (Vps18) suppresses epithelial growth factor receptor (EGFR) expression and lung tumorigenesis. The Journal of biological chemistry 1 40615043
2015 Dendritic cells induce specific cytotoxic T lymphocytes against prostate cancer TRAMP-C2 cells loaded with freeze- thaw antigen and PEP-3 peptide. Asian Pacific journal of cancer prevention : APJCP 1 25684489
2026 Mutations in VPS18 lead to a neutrophil maturation defect associated with disturbed vesicle homeostasis. Cell death & disease 0 41526335