{"gene":"VPS18","run_date":"2026-06-11T09:02:06","timeline":{"discoveries":[{"year":1991,"finding":"PEP3/VPS18 encodes a hydrophilic 107-kDa vacuolar peripheral membrane protein required for vacuolar biogenesis in S. cerevisiae; deletion causes accumulation of small vesicles, loss of vacuolar morphology, and defects in delivery of carboxypeptidase Y, protease A, protease B, and alkaline phosphatase. Cell fractionation showed the protein is present at low abundance in both log-phase and stationary cells as a vacuolar peripheral membrane protein.","method":"Gene cloning by complementation, deletion/disruption alleles, cell fractionation of PEP3::SUC2 fusion protein, fluorescence and electron microscopy","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (genetic complementation, fractionation, EM, fluorescence microscopy) in a foundational study establishing the protein's localization and function","pmids":["1944264"],"is_preprint":false},{"year":2001,"finding":"Aspergillus nidulans DigA (homolog of Pep3/Vps18) localizes to the cytoplasm and contains a clathrin repeat motif, two coiled-coil regions, and a RING finger Zn-binding motif at the C-terminus; digA mutants display clustered mitochondria, clustered nuclei, and defects in actin cytoskeleton polarization, indicating vacuolar function is required for organelle positioning and polarized growth.","method":"Gene cloning, HA-epitope tagging and secondary immunofluorescence localization, mutant phenotype analysis (nuclear migration screen)","journal":"Molecular genetics and genomics : MGG","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — single lab, immunofluorescence localization with functional phenotype in a fungal ortholog, consistent with mammalian gene function","pmids":["11810240"],"is_preprint":false},{"year":2005,"finding":"Loss-of-function mutation of zebrafish vps18 (a class C vacuolar protein sorting gene) causes hepatomegaly with large vesicle-filled hepatocytes, defects in bile canaliculi, and biliary paucity, attributed to failure of endosomal-lysosomal trafficking and defective vesicle trafficking to the hepatocyte apical membrane.","method":"Zebrafish insertional mutant screen, histology, light microscopy of liver phenotype","journal":"Development (Cambridge, England)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic loss-of-function in zebrafish ortholog with specific cellular and tissue phenotypes, single lab","pmids":["16000385"],"is_preprint":false},{"year":2006,"finding":"In zebrafish vps18 mutant (vps18hi2499A), a retroviral insertion at exon 4 produces two abnormal splicing variants lacking the clathrin repeat and RING finger conserved domains. Vps18 deficiency results in drastically reduced melanosome numbers in the retinal pigmented epithelium and accumulation of immature melanosomes, demonstrating Vps18 is required for melanosome biogenesis as part of the HOPS complex involved in endosomal/lysosomal tethering.","method":"Insertional mutant characterization, RT-PCR splicing analysis, electron microscopy of melanosomes, optokinetic response assay","journal":"Pigment cell research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic loss-of-function with organelle-level phenotype, multiple assays, single lab","pmids":["16827750"],"is_preprint":false},{"year":2008,"finding":"C. elegans VPS-18 is required in engulfing cells for phagosome-lysosome fusion; vps-18 deletion causes accumulation of undegraded apoptotic cell corpses, defects in endosome and lysosome biogenesis, and failure of phagosomes containing cell corpses to fuse with lysosomes.","method":"C. elegans deletion mutant analysis, fluorescence microscopy of phagosome-lysosome fusion, cell corpse accumulation assay","journal":"Molecular biology of the cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic loss-of-function with direct visualization of phagosome-lysosome fusion defect, multiple orthogonal assays, mechanistically informative","pmids":["18923146"],"is_preprint":false},{"year":2011,"finding":"Vps18 is required for efficient HIV-1 Gag targeting to the plasma membrane and infectious virion production; depletion of human VPS18 reduces infectious HIV-1 particle release in human cells, identified through a yeast genetic screen and validated in mammalian cells.","method":"Yeast genetic screen for Gag plasma membrane targeting defects, siRNA knockdown of hVPS18 in human cells, VLP release assay","journal":"Journal of virology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — two-organism validation (yeast screen + human cell knockdown), single lab, specific functional readout","pmids":["21450827"],"is_preprint":false},{"year":2012,"finding":"Conditional knockout of Vps18 in neural cells (Vps18F/F; Nestin-Cre mice) causes severe neurodegeneration and neuronal migration defects by blocking multiple vesicle transport pathways to the lysosome including autophagy, endocytosis, and biosynthetic pathways. Vps18 deficiency leads to up-regulation of β1 integrin due to lysosomal dysfunction; knockdown of β1 integrin partially rescues neuronal migration defects, placing Vps18 upstream of β1 integrin in migration regulation.","method":"Conditional knockout mouse model, epistasis (β1 integrin knockdown rescue), Western blot, immunofluorescence, autophagy/endocytosis/biosynthetic pathway assays","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — conditional knockout with epistasis rescue experiment, multiple pathway assays, multiple orthogonal methods in single rigorous study","pmids":["22854957"],"is_preprint":false},{"year":2012,"finding":"Vps18 deficiency in Purkinje cells blocks dendrite development by preventing lysosomal degradation of Lysyl Oxidase (Lox); Lox protein accumulates in Vps18-deficient cerebellum due to lysosomal dysfunction, linking the lysosomal degradative function of Vps18 to dendritogenesis.","method":"Conditional knockout mouse analysis, Western blot demonstrating Lox accumulation, immunofluorescence","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic loss-of-function with identification of specific substrate (Lox) accumulated due to lysosomal dysfunction, single lab, two methods","pmids":["22699122"],"is_preprint":false},{"year":2017,"finding":"Human VPS18 recruits VPS41 to the HOPS complex via a direct RING-RING domain interaction; the zinc-containing RING domains of VPS18 and VPS41 form a stable heterodimer in vitro, and the VPS18 RING domain is required to integrate VPS41 into endogenous HOPS complexes in cells. This mechanism is not conserved in yeast, as yeast Vps41 lacks a C-terminal zinc-finger motif.","method":"Biochemical pulldown/co-purification of recombinant RING domains, co-immunoprecipitation from cells, domain truncation/mutagenesis analysis","journal":"The Biochemical journal","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro reconstitution of RING-RING heterodimer plus cell-based co-IP validation and domain mutagenesis, multiple orthogonal methods","pmids":["28931724"],"is_preprint":false},{"year":2019,"finding":"VPS18 (and VPS11) function as E3 ubiquitin ligases, in addition to their role in HOPS/CORVET endosomal fusion complexes. Overexpression of Vps11/Vps18 perturbs ubiquitination in signal transduction pathways including Wnt, estrogen receptor α (ERα), and NFκB. Specifically, Vps11/18-mediated ubiquitination of the scaffold protein PELP1 impairs ERα activation by c-Src.","method":"Overexpression experiments, ubiquitination assays, co-immunoprecipitation, signaling pathway readouts (Wnt, ERα, NFκB)","journal":"Nature communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple signaling pathways tested, specific substrate (PELP1) identified, ubiquitination assays plus co-IP, single lab","pmids":["31015428"],"is_preprint":false},{"year":2024,"finding":"VPS18 (with VPS11) interacts with PD-L1 in endosomes, promotes PD-L1 glycosylation and protein stability, and mediates trans-Golgi network recycling of PD-L1; VPS18 deficiency reduces PD-L1 protein stability and enhances antitumor immune response. A VPS18 inhibitor (RDN) impairs PD-L1 trafficking and stability.","method":"Co-immunoprecipitation, VPS18 knockdown/knockout, Western blot for PD-L1 glycosylation and stability, pharmacological inhibition, in vivo tumor models","journal":"Science advances","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP, KO with defined molecular phenotype (PD-L1 stability), pharmacological validation, single lab, multiple methods","pmids":["39413192"],"is_preprint":false},{"year":2025,"finding":"VPS18 colocalizes with Mycobacterium tuberculosis-containing phagosomes in macrophages shortly after infection and is required for phagosomal membrane integrity; VPS18-knockout macrophages show increased Mtb phagosome damage without impaired autophagy, and Mtb grows more robustly in VPS18-KO cells.","method":"Genome-wide CRISPR screen, VPS18 KO macrophages, fluorescence colocalization, phagosome integrity assay, bacterial growth assay","journal":"Science advances","confidence":"High","confidence_rationale":"Tier 2 / Strong — genome-wide unbiased CRISPR screen followed by KO validation with multiple functional readouts (colocalization, membrane integrity, bacterial growth), replicated from preprint","pmids":["39888996"],"is_preprint":false},{"year":2025,"finding":"Vps18 suppresses lung tumorigenesis by promoting lysosomal degradation of EGFR; Vps18 genetic ablation in LSL-K-Ras mice elevates EGFR protein levels and activates ERK-MAPK signaling. Expression of dominant-negative EGFR partially suppresses tumor-promoting effects of Vps18 loss, placing Vps18 upstream of EGFR-ERK in a tumor suppressor axis.","method":"Conditional knockout in LSL-K-Ras mice, epistasis with dominant-negative EGFR, Western blot for EGFR and ERK activation, tumor growth assays","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic epistasis (dnEGFR rescue) plus KO tumor model, single lab, two orthogonal methods","pmids":["40615043"],"is_preprint":false},{"year":2026,"finding":"VPS18 deficiency in neutrophil progenitors (CRISPR/Cas9 Hoxb8 cells) causes HOPS/CORVET tethering complex instability, impaired vesicle dynamics, autophagosome accumulation (elevated LC3B-II and p62), reduced autophagic flux, and premature apoptosis, blocking neutrophil maturation. Human iPSCs with VPS18 loss also fail to generate neutrophils. A patient with a heterozygous stop-gain VPS18 mutation presents with neutropenia.","method":"CRISPR/Cas9 knockin Hoxb8 cells, iPSC differentiation, transmission electron microscopy, Western blot (LC3B-II, p62), zebrafish vps18 heterozygous mutants, patient mutation analysis","journal":"Cell death & disease","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple model systems (mouse cells, human iPSCs, zebrafish, patient), multiple orthogonal methods (TEM, Western blot, genetic), consistent mechanistic findings across systems","pmids":["41526335"],"is_preprint":false}],"current_model":"VPS18 is a central core subunit of the HOPS and CORVET endosomal membrane tethering complexes that mediates multiple vesicle transport pathways to lysosomes (endocytosis, autophagy, biosynthetic pathway); its C-terminal RING domain directly recruits VPS41 to assemble the HOPS complex, and it additionally functions as an E3 ubiquitin ligase to fine-tune signaling through substrates such as PELP1; loss of VPS18 disrupts lysosomal degradation of specific cargo (EGFR, Lysyl Oxidase, PD-L1), impairs phagosome-lysosome fusion (including in Mtb-infected macrophages), blocks autophagosome clearance, and causes diverse cell-type-specific phenotypes including neurodegeneration, neuronal migration defects, melanosome biogenesis failure, neutrophil maturation arrest, and enhanced tumorigenesis."},"narrative":{"mechanistic_narrative":"VPS18 is a core subunit of the HOPS and CORVET endosomal membrane-tethering complexes that drives the delivery of cargo to the lysosome/vacuole through endocytic, autophagic, biosynthetic, and phagocytic routes, and is conserved from yeast vacuolar biogenesis to mammalian lysosomal function [PMID:1944264, PMID:22854957, PMID:41526335]. In humans, its C-terminal RING domain forms a zinc-dependent RING-RING heterodimer with VPS41 that integrates VPS41 into endogenous HOPS complexes, a recruitment mechanism not conserved in yeast [PMID:28931724]. Beyond tethering, VPS18 acts as an E3 ubiquitin ligase that modulates signaling, ubiquitinating the scaffold PELP1 to restrain ERα activation [PMID:31015428]. Through its control of lysosomal degradation, VPS18 governs the turnover of specific cargo: it promotes lysosomal degradation of EGFR to suppress ERK-MAPK signaling and lung tumorigenesis [PMID:40615043], degrades Lysyl Oxidase to permit Purkinje-cell dendritogenesis [PMID:22699122], and conversely stabilizes PD-L1 by promoting its glycosylation and trans-Golgi recycling, such that VPS18 loss enhances antitumor immunity [PMID:39413192]. VPS18 is also required for phagosome-lysosome fusion and phagosomal membrane integrity, including restriction of Mycobacterium tuberculosis in macrophages [PMID:18923146, PMID:39888996]. Loss of VPS18 produces cell-type-specific phenotypes spanning neurodegeneration and neuronal migration defects (acting upstream of β1 integrin) [PMID:22854957], melanosome biogenesis failure [PMID:16827750], and a neutrophil maturation arrest associated with autophagosome accumulation and a patient presenting with neutropenia [PMID:41526335].","teleology":[{"year":1991,"claim":"Established the founding function of VPS18 as a vacuolar peripheral membrane protein required for organelle biogenesis and hydrolase delivery, defining the protein's core trafficking role.","evidence":"Gene cloning by complementation, deletion alleles, cell fractionation, and EM/fluorescence microscopy in S. cerevisiae","pmids":["1944264"],"confidence":"High","gaps":["Did not define molecular partners or complex membership","No mechanism for how the protein supports vacuole formation"]},{"year":2001,"claim":"Defined the conserved domain architecture (clathrin repeat, coiled-coils, C-terminal RING zinc finger) and linked vacuolar function to organelle positioning and polarized growth in a fungal ortholog.","evidence":"Gene cloning, HA-tagging immunofluorescence, and nuclear migration mutant phenotyping in A. nidulans","pmids":["11810240"],"confidence":"Medium","gaps":["RING domain function not biochemically tested","Single fungal system, not validated in mammals"]},{"year":2005,"claim":"Showed at the organismal level that vps18 loss disrupts endosomal-lysosomal trafficking and apical membrane delivery, producing tissue-specific liver pathology.","evidence":"Zebrafish insertional mutant histology and light microscopy of liver","pmids":["16000385"],"confidence":"Medium","gaps":["Molecular trafficking step affected not pinpointed","No cargo identified"]},{"year":2006,"claim":"Connected VPS18/HOPS-mediated endolysosomal tethering to lysosome-related organelle biogenesis by demonstrating a requirement for melanosome maturation.","evidence":"Zebrafish insertional mutant with splicing analysis, EM of melanosomes, optokinetic assay","pmids":["16827750"],"confidence":"Medium","gaps":["Direct role in melanosome cargo delivery not resolved","HOPS complex membership inferred, not biochemically shown here"]},{"year":2008,"claim":"Demonstrated that VPS18 is required in engulfing cells for phagosome-lysosome fusion, extending its function beyond endosome biogenesis to corpse clearance.","evidence":"C. elegans deletion mutant analysis with fluorescence microscopy of phagosome-lysosome fusion and corpse accumulation","pmids":["18923146"],"confidence":"High","gaps":["Tethering versus fusion contribution not separated","No physical partners mapped"]},{"year":2011,"claim":"Implicated human VPS18 in viral assembly by showing it is needed for HIV-1 Gag plasma membrane targeting and infectious virion production.","evidence":"Yeast genetic screen plus siRNA knockdown of hVPS18 and VLP release assay in human cells","pmids":["21450827"],"confidence":"Medium","gaps":["Direct interaction with Gag not established","Mechanism linking endolysosomal tethering to PM targeting unclear"]},{"year":2012,"claim":"Established in mammals that VPS18 controls neuronal viability and migration by enabling multiple vesicle transport routes to the lysosome, acting upstream of β1 integrin and the degradation of Lysyl Oxidase.","evidence":"Conditional knockout mice with epistasis rescue (β1 integrin knockdown; Lox accumulation), Western blot, immunofluorescence, pathway assays","pmids":["22854957","22699122"],"confidence":"High","gaps":["Whether VPS18 directly degrades these substrates or acts via general lysosomal failure not separated","Cell-autonomous mechanism of migration regulation incomplete"]},{"year":2017,"claim":"Resolved the molecular basis of HOPS assembly in humans, showing VPS18's RING domain directly recruits VPS41 via a zinc-dependent RING-RING heterodimer not conserved in yeast.","evidence":"In vitro co-purification of recombinant RING domains, cell co-IP, and domain truncation/mutagenesis","pmids":["28931724"],"confidence":"High","gaps":["Full HOPS subunit arrangement not solved structurally","Functional consequence of the RING-RING interaction for tethering not directly tested"]},{"year":2019,"claim":"Revealed a moonlighting E3 ubiquitin ligase activity for VPS18 that modulates signaling pathways, with PELP1 identified as a substrate restraining ERα activation.","evidence":"Overexpression and ubiquitination assays, co-IP, and Wnt/ERα/NF-κB signaling readouts","pmids":["31015428"],"confidence":"Medium","gaps":["Relies on overexpression; endogenous ligase activity not quantified","Catalytic residues and substrate range not fully mapped"]},{"year":2024,"claim":"Showed VPS18 stabilizes PD-L1 through endosomal interaction, glycosylation, and trans-Golgi recycling, defining a druggable axis linking VPS18 to antitumor immunity.","evidence":"Co-IP, VPS18 knockdown/knockout, Western blot for glycosylation/stability, pharmacological inhibition (RDN), in vivo tumor models","pmids":["39413192"],"confidence":"Medium","gaps":["Direct versus complex-mediated PD-L1 engagement unresolved","Inhibitor selectivity for VPS18 not fully characterized"]},{"year":2025,"claim":"Defined opposing roles in cancer and infection: VPS18 suppresses lung tumorigenesis via lysosomal degradation of EGFR, and protects against M. tuberculosis by maintaining phagosomal membrane integrity.","evidence":"Conditional KO in LSL-K-Ras mice with dnEGFR epistasis; genome-wide CRISPR screen with KO macrophage colocalization, integrity and bacterial growth assays","pmids":["40615043","39888996"],"confidence":"High","gaps":["Mechanism by which VPS18 preserves phagosomal membrane integrity unknown","Whether EGFR degradation is direct HOPS cargo handling or ligase-dependent not separated"]},{"year":2026,"claim":"Linked VPS18 to human hematopoietic disease, showing its loss destabilizes HOPS/CORVET, blocks autophagic flux and neutrophil maturation, with a patient stop-gain mutation presenting as neutropenia.","evidence":"CRISPR Hoxb8 cells, iPSC differentiation, TEM, Western blot (LC3B-II, p62), zebrafish heterozygotes, patient mutation analysis","pmids":["41526335"],"confidence":"High","gaps":["Causality of the patient variant not formally proven by rescue","Why neutrophil lineage is selectively vulnerable not explained"]},{"year":null,"claim":"How VPS18's tethering, RING-mediated assembly, and E3 ligase activities are coordinated at distinct membranes and which functions are direct versus secondary to general lysosomal failure remain unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structure of the assembled mammalian HOPS/CORVET complex","Substrate spectrum of the ligase activity undefined","Direct cargo recognition mechanisms for EGFR, PD-L1, and Lox not established"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0016874","term_label":"ligase activity","supporting_discovery_ids":[9]},{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[9]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[8]}],"localization":[{"term_id":"GO:0005768","term_label":"endosome","supporting_discovery_ids":[4,10]},{"term_id":"GO:0005764","term_label":"lysosome","supporting_discovery_ids":[0,4]},{"term_id":"GO:0005773","term_label":"vacuole","supporting_discovery_ids":[0]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[1]}],"pathway":[{"term_id":"R-HSA-5653656","term_label":"Vesicle-mediated transport","supporting_discovery_ids":[0,4,6]},{"term_id":"R-HSA-9612973","term_label":"Autophagy","supporting_discovery_ids":[6,13]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[9,12]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[10,11]}],"complexes":["HOPS","CORVET"],"partners":["VPS41","VPS11","PELP1","PD-L1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q9P253","full_name":"Vacuolar protein sorting-associated protein 18 homolog","aliases":[],"length_aa":973,"mass_kda":110.2,"function":"Plays a role in vesicle-mediated protein trafficking to lysosomal compartments including the endocytic membrane transport and autophagic pathways. Believed to act as a core component of the putative HOPS and CORVET endosomal tethering complexes which are proposed to be involved in the Rab5-to-Rab7 endosome conversion probably implicating MON1A/B, and via binding SNAREs and SNARE complexes to mediate tethering and docking events during SNARE-mediated membrane fusion. The HOPS complex is proposed to be recruited to Rab7 on the late endosomal membrane and to regulate late endocytic, phagocytic and autophagic traffic towards lysosomes. The CORVET complex is proposed to function as a Rab5 effector to mediate early endosome fusion probably in specific endosome subpopulations (PubMed:11382755, PubMed:23351085, PubMed:24554770, PubMed:25783203). Required for fusion of endosomes and autophagosomes with lysosomes (PubMed:25783203). Involved in dendrite development of Pukinje cells (By similarity)","subcellular_location":"Late endosome membrane; Lysosome membrane; Early endosome; Cytoplasmic vesicle, autophagosome; Cytoplasmic vesicle, clathrin-coated vesicle","url":"https://www.uniprot.org/uniprotkb/Q9P253/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":true,"resolved_as":"","url":"https://depmap.org/portal/gene/VPS18","classification":"Common Essential","n_dependent_lines":1126,"n_total_lines":1208,"dependency_fraction":0.9321192052980133},"opencell":{"profiled":true,"resolved_as":"","ensg_id":"ENSG00000104142","cell_line_id":"CID001858","localizations":[{"compartment":"cytoplasmic","grade":3},{"compartment":"vesicles","grade":3}],"interactors":[{"gene":"VPS41","stoichiometry":10.0},{"gene":"VPS8","stoichiometry":10.0},{"gene":"VPS11","stoichiometry":10.0},{"gene":"VPS16","stoichiometry":10.0},{"gene":"TGFBRAP1","stoichiometry":10.0},{"gene":"VPS33A","stoichiometry":10.0},{"gene":"LSG1","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/target/CID001858","total_profiled":1310},"omim":[{"mim_id":"620229","title":"FHF COMPLEX SUBUNIT HOOK-INTERACTING PROTEIN 1B; FHIP1B","url":"https://www.omim.org/entry/620229"},{"mim_id":"619389","title":"SPINOCEREBELLAR ATAXIA, AUTOSOMAL RECESSIVE 29; SCAR29","url":"https://www.omim.org/entry/619389"},{"mim_id":"617303","title":"MUCOPOLYSACCHARIDOSIS-PLUS SYNDROME; MPSPS","url":"https://www.omim.org/entry/617303"},{"mim_id":"616683","title":"LEUKODYSTROPHY, HYPOMYELINATING, 12; HLD12","url":"https://www.omim.org/entry/616683"},{"mim_id":"616303","title":"WD REPEAT-CONTAINING PROTEIN 91; WDR91","url":"https://www.omim.org/entry/616303"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/VPS18"},"hgnc":{"alias_symbol":["KIAA1475","PEP3"],"prev_symbol":[]},"alphafold":{"accession":"Q9P253","domains":[{"cath_id":"-","chopping":"92-224_227-260","consensus_level":"medium","plddt":86.5422,"start":92,"end":260},{"cath_id":"1.25.40","chopping":"553-806","consensus_level":"medium","plddt":73.305,"start":553,"end":806},{"cath_id":"-","chopping":"851-901_930-973","consensus_level":"medium","plddt":81.6057,"start":851,"end":973},{"cath_id":"1.25.40","chopping":"398-549","consensus_level":"medium","plddt":80.4134,"start":398,"end":549}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9P253","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9P253-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9P253-F1-predicted_aligned_error_v6.png","plddt_mean":78.81},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=VPS18","jax_strain_url":"https://www.jax.org/strain/search?query=VPS18"},"sequence":{"accession":"Q9P253","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9P253.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9P253/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9P253"}},"corpus_meta":[{"pmid":"16000385","id":"PMC_16000385","title":"A genetic screen in zebrafish identifies the mutants vps18, nf2 and foie gras as models of liver disease.","date":"2005","source":"Development (Cambridge, England)","url":"https://pubmed.ncbi.nlm.nih.gov/16000385","citation_count":150,"is_preprint":false},{"pmid":"1944264","id":"PMC_1944264","title":"Isolation and characterization of PEP3, a gene required for vacuolar biogenesis in Saccharomyces cerevisiae.","date":"1991","source":"Molecular and cellular biology","url":"https://pubmed.ncbi.nlm.nih.gov/1944264","citation_count":64,"is_preprint":false},{"pmid":"11250079","id":"PMC_11250079","title":"Molecular cloning and characterization of human VPS18, VPS 11, VPS16, and VPS33.","date":"2001","source":"Gene","url":"https://pubmed.ncbi.nlm.nih.gov/11250079","citation_count":59,"is_preprint":false},{"pmid":"18923146","id":"PMC_18923146","title":"Lysosome biogenesis mediated by vps-18 affects apoptotic cell degradation in Caenorhabditis elegans.","date":"2008","source":"Molecular biology of 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sciences","url":"https://pubmed.ncbi.nlm.nih.gov/36066153","citation_count":3,"is_preprint":false},{"pmid":"40615043","id":"PMC_40615043","title":"Vacuole protein sorting 18 (Vps18) suppresses epithelial growth factor receptor (EGFR) expression and lung tumorigenesis.","date":"2025","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/40615043","citation_count":1,"is_preprint":false},{"pmid":"25684489","id":"PMC_25684489","title":"Dendritic cells induce specific cytotoxic T lymphocytes against prostate cancer TRAMP-C2 cells loaded with freeze- thaw antigen and PEP-3 peptide.","date":"2015","source":"Asian Pacific journal of cancer prevention : APJCP","url":"https://pubmed.ncbi.nlm.nih.gov/25684489","citation_count":1,"is_preprint":false},{"pmid":"41526335","id":"PMC_41526335","title":"Mutations in VPS18 lead to a neutrophil maturation defect associated with disturbed vesicle homeostasis.","date":"2026","source":"Cell death & disease","url":"https://pubmed.ncbi.nlm.nih.gov/41526335","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2025.08.15.670286","title":"Mutations in  <i>VPS18</i>  lead to a neutrophil maturation defect associated with disturbed vesicle homeostasis","date":"2025-08-21","source":"bioRxiv","url":"https://doi.org/10.1101/2025.08.15.670286","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2024.07.17.603885","title":"A powdery mildew core effector protein targets host endosome tethering complexes HOPS and CORVET","date":"2024-07-22","source":"bioRxiv","url":"https://doi.org/10.1101/2024.07.17.603885","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":13570,"output_tokens":3848,"usd":0.049215,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":11640,"output_tokens":4035,"usd":0.079537,"stage2_stop_reason":"end_turn"},"total_usd":0.128752,"stage1_batch_id":"msgbatch_01UT1AahFPCAyn2uVweS7A9z","stage2_batch_id":"msgbatch_01HuKWtKNT4Pqj1bc8eEP5RV","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1991,\n      \"finding\": \"PEP3/VPS18 encodes a hydrophilic 107-kDa vacuolar peripheral membrane protein required for vacuolar biogenesis in S. cerevisiae; deletion causes accumulation of small vesicles, loss of vacuolar morphology, and defects in delivery of carboxypeptidase Y, protease A, protease B, and alkaline phosphatase. Cell fractionation showed the protein is present at low abundance in both log-phase and stationary cells as a vacuolar peripheral membrane protein.\",\n      \"method\": \"Gene cloning by complementation, deletion/disruption alleles, cell fractionation of PEP3::SUC2 fusion protein, fluorescence and electron microscopy\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (genetic complementation, fractionation, EM, fluorescence microscopy) in a foundational study establishing the protein's localization and function\",\n      \"pmids\": [\"1944264\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"Aspergillus nidulans DigA (homolog of Pep3/Vps18) localizes to the cytoplasm and contains a clathrin repeat motif, two coiled-coil regions, and a RING finger Zn-binding motif at the C-terminus; digA mutants display clustered mitochondria, clustered nuclei, and defects in actin cytoskeleton polarization, indicating vacuolar function is required for organelle positioning and polarized growth.\",\n      \"method\": \"Gene cloning, HA-epitope tagging and secondary immunofluorescence localization, mutant phenotype analysis (nuclear migration screen)\",\n      \"journal\": \"Molecular genetics and genomics : MGG\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — single lab, immunofluorescence localization with functional phenotype in a fungal ortholog, consistent with mammalian gene function\",\n      \"pmids\": [\"11810240\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"Loss-of-function mutation of zebrafish vps18 (a class C vacuolar protein sorting gene) causes hepatomegaly with large vesicle-filled hepatocytes, defects in bile canaliculi, and biliary paucity, attributed to failure of endosomal-lysosomal trafficking and defective vesicle trafficking to the hepatocyte apical membrane.\",\n      \"method\": \"Zebrafish insertional mutant screen, histology, light microscopy of liver phenotype\",\n      \"journal\": \"Development (Cambridge, England)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic loss-of-function in zebrafish ortholog with specific cellular and tissue phenotypes, single lab\",\n      \"pmids\": [\"16000385\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"In zebrafish vps18 mutant (vps18hi2499A), a retroviral insertion at exon 4 produces two abnormal splicing variants lacking the clathrin repeat and RING finger conserved domains. Vps18 deficiency results in drastically reduced melanosome numbers in the retinal pigmented epithelium and accumulation of immature melanosomes, demonstrating Vps18 is required for melanosome biogenesis as part of the HOPS complex involved in endosomal/lysosomal tethering.\",\n      \"method\": \"Insertional mutant characterization, RT-PCR splicing analysis, electron microscopy of melanosomes, optokinetic response assay\",\n      \"journal\": \"Pigment cell research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic loss-of-function with organelle-level phenotype, multiple assays, single lab\",\n      \"pmids\": [\"16827750\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"C. elegans VPS-18 is required in engulfing cells for phagosome-lysosome fusion; vps-18 deletion causes accumulation of undegraded apoptotic cell corpses, defects in endosome and lysosome biogenesis, and failure of phagosomes containing cell corpses to fuse with lysosomes.\",\n      \"method\": \"C. elegans deletion mutant analysis, fluorescence microscopy of phagosome-lysosome fusion, cell corpse accumulation assay\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic loss-of-function with direct visualization of phagosome-lysosome fusion defect, multiple orthogonal assays, mechanistically informative\",\n      \"pmids\": [\"18923146\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Vps18 is required for efficient HIV-1 Gag targeting to the plasma membrane and infectious virion production; depletion of human VPS18 reduces infectious HIV-1 particle release in human cells, identified through a yeast genetic screen and validated in mammalian cells.\",\n      \"method\": \"Yeast genetic screen for Gag plasma membrane targeting defects, siRNA knockdown of hVPS18 in human cells, VLP release assay\",\n      \"journal\": \"Journal of virology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — two-organism validation (yeast screen + human cell knockdown), single lab, specific functional readout\",\n      \"pmids\": [\"21450827\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Conditional knockout of Vps18 in neural cells (Vps18F/F; Nestin-Cre mice) causes severe neurodegeneration and neuronal migration defects by blocking multiple vesicle transport pathways to the lysosome including autophagy, endocytosis, and biosynthetic pathways. Vps18 deficiency leads to up-regulation of β1 integrin due to lysosomal dysfunction; knockdown of β1 integrin partially rescues neuronal migration defects, placing Vps18 upstream of β1 integrin in migration regulation.\",\n      \"method\": \"Conditional knockout mouse model, epistasis (β1 integrin knockdown rescue), Western blot, immunofluorescence, autophagy/endocytosis/biosynthetic pathway assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — conditional knockout with epistasis rescue experiment, multiple pathway assays, multiple orthogonal methods in single rigorous study\",\n      \"pmids\": [\"22854957\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Vps18 deficiency in Purkinje cells blocks dendrite development by preventing lysosomal degradation of Lysyl Oxidase (Lox); Lox protein accumulates in Vps18-deficient cerebellum due to lysosomal dysfunction, linking the lysosomal degradative function of Vps18 to dendritogenesis.\",\n      \"method\": \"Conditional knockout mouse analysis, Western blot demonstrating Lox accumulation, immunofluorescence\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic loss-of-function with identification of specific substrate (Lox) accumulated due to lysosomal dysfunction, single lab, two methods\",\n      \"pmids\": [\"22699122\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Human VPS18 recruits VPS41 to the HOPS complex via a direct RING-RING domain interaction; the zinc-containing RING domains of VPS18 and VPS41 form a stable heterodimer in vitro, and the VPS18 RING domain is required to integrate VPS41 into endogenous HOPS complexes in cells. This mechanism is not conserved in yeast, as yeast Vps41 lacks a C-terminal zinc-finger motif.\",\n      \"method\": \"Biochemical pulldown/co-purification of recombinant RING domains, co-immunoprecipitation from cells, domain truncation/mutagenesis analysis\",\n      \"journal\": \"The Biochemical journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro reconstitution of RING-RING heterodimer plus cell-based co-IP validation and domain mutagenesis, multiple orthogonal methods\",\n      \"pmids\": [\"28931724\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"VPS18 (and VPS11) function as E3 ubiquitin ligases, in addition to their role in HOPS/CORVET endosomal fusion complexes. Overexpression of Vps11/Vps18 perturbs ubiquitination in signal transduction pathways including Wnt, estrogen receptor α (ERα), and NFκB. Specifically, Vps11/18-mediated ubiquitination of the scaffold protein PELP1 impairs ERα activation by c-Src.\",\n      \"method\": \"Overexpression experiments, ubiquitination assays, co-immunoprecipitation, signaling pathway readouts (Wnt, ERα, NFκB)\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple signaling pathways tested, specific substrate (PELP1) identified, ubiquitination assays plus co-IP, single lab\",\n      \"pmids\": [\"31015428\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"VPS18 (with VPS11) interacts with PD-L1 in endosomes, promotes PD-L1 glycosylation and protein stability, and mediates trans-Golgi network recycling of PD-L1; VPS18 deficiency reduces PD-L1 protein stability and enhances antitumor immune response. A VPS18 inhibitor (RDN) impairs PD-L1 trafficking and stability.\",\n      \"method\": \"Co-immunoprecipitation, VPS18 knockdown/knockout, Western blot for PD-L1 glycosylation and stability, pharmacological inhibition, in vivo tumor models\",\n      \"journal\": \"Science advances\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP, KO with defined molecular phenotype (PD-L1 stability), pharmacological validation, single lab, multiple methods\",\n      \"pmids\": [\"39413192\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"VPS18 colocalizes with Mycobacterium tuberculosis-containing phagosomes in macrophages shortly after infection and is required for phagosomal membrane integrity; VPS18-knockout macrophages show increased Mtb phagosome damage without impaired autophagy, and Mtb grows more robustly in VPS18-KO cells.\",\n      \"method\": \"Genome-wide CRISPR screen, VPS18 KO macrophages, fluorescence colocalization, phagosome integrity assay, bacterial growth assay\",\n      \"journal\": \"Science advances\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genome-wide unbiased CRISPR screen followed by KO validation with multiple functional readouts (colocalization, membrane integrity, bacterial growth), replicated from preprint\",\n      \"pmids\": [\"39888996\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Vps18 suppresses lung tumorigenesis by promoting lysosomal degradation of EGFR; Vps18 genetic ablation in LSL-K-Ras mice elevates EGFR protein levels and activates ERK-MAPK signaling. Expression of dominant-negative EGFR partially suppresses tumor-promoting effects of Vps18 loss, placing Vps18 upstream of EGFR-ERK in a tumor suppressor axis.\",\n      \"method\": \"Conditional knockout in LSL-K-Ras mice, epistasis with dominant-negative EGFR, Western blot for EGFR and ERK activation, tumor growth assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic epistasis (dnEGFR rescue) plus KO tumor model, single lab, two orthogonal methods\",\n      \"pmids\": [\"40615043\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"VPS18 deficiency in neutrophil progenitors (CRISPR/Cas9 Hoxb8 cells) causes HOPS/CORVET tethering complex instability, impaired vesicle dynamics, autophagosome accumulation (elevated LC3B-II and p62), reduced autophagic flux, and premature apoptosis, blocking neutrophil maturation. Human iPSCs with VPS18 loss also fail to generate neutrophils. A patient with a heterozygous stop-gain VPS18 mutation presents with neutropenia.\",\n      \"method\": \"CRISPR/Cas9 knockin Hoxb8 cells, iPSC differentiation, transmission electron microscopy, Western blot (LC3B-II, p62), zebrafish vps18 heterozygous mutants, patient mutation analysis\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple model systems (mouse cells, human iPSCs, zebrafish, patient), multiple orthogonal methods (TEM, Western blot, genetic), consistent mechanistic findings across systems\",\n      \"pmids\": [\"41526335\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"VPS18 is a central core subunit of the HOPS and CORVET endosomal membrane tethering complexes that mediates multiple vesicle transport pathways to lysosomes (endocytosis, autophagy, biosynthetic pathway); its C-terminal RING domain directly recruits VPS41 to assemble the HOPS complex, and it additionally functions as an E3 ubiquitin ligase to fine-tune signaling through substrates such as PELP1; loss of VPS18 disrupts lysosomal degradation of specific cargo (EGFR, Lysyl Oxidase, PD-L1), impairs phagosome-lysosome fusion (including in Mtb-infected macrophages), blocks autophagosome clearance, and causes diverse cell-type-specific phenotypes including neurodegeneration, neuronal migration defects, melanosome biogenesis failure, neutrophil maturation arrest, and enhanced tumorigenesis.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"VPS18 is a core subunit of the HOPS and CORVET endosomal membrane-tethering complexes that drives the delivery of cargo to the lysosome/vacuole through endocytic, autophagic, biosynthetic, and phagocytic routes, and is conserved from yeast vacuolar biogenesis to mammalian lysosomal function [#0, #6, #13]. In humans, its C-terminal RING domain forms a zinc-dependent RING-RING heterodimer with VPS41 that integrates VPS41 into endogenous HOPS complexes, a recruitment mechanism not conserved in yeast [#8]. Beyond tethering, VPS18 acts as an E3 ubiquitin ligase that modulates signaling, ubiquitinating the scaffold PELP1 to restrain ERα activation [#9]. Through its control of lysosomal degradation, VPS18 governs the turnover of specific cargo: it promotes lysosomal degradation of EGFR to suppress ERK-MAPK signaling and lung tumorigenesis [#12], degrades Lysyl Oxidase to permit Purkinje-cell dendritogenesis [#7], and conversely stabilizes PD-L1 by promoting its glycosylation and trans-Golgi recycling, such that VPS18 loss enhances antitumor immunity [#10]. VPS18 is also required for phagosome-lysosome fusion and phagosomal membrane integrity, including restriction of Mycobacterium tuberculosis in macrophages [#4, #11]. Loss of VPS18 produces cell-type-specific phenotypes spanning neurodegeneration and neuronal migration defects (acting upstream of β1 integrin) [#6], melanosome biogenesis failure [#3], and a neutrophil maturation arrest associated with autophagosome accumulation and a patient presenting with neutropenia [#13].\",\n  \"teleology\": [\n    {\n      \"year\": 1991,\n      \"claim\": \"Established the founding function of VPS18 as a vacuolar peripheral membrane protein required for organelle biogenesis and hydrolase delivery, defining the protein's core trafficking role.\",\n      \"evidence\": \"Gene cloning by complementation, deletion alleles, cell fractionation, and EM/fluorescence microscopy in S. cerevisiae\",\n      \"pmids\": [\"1944264\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not define molecular partners or complex membership\", \"No mechanism for how the protein supports vacuole formation\"]\n    },\n    {\n      \"year\": 2001,\n      \"claim\": \"Defined the conserved domain architecture (clathrin repeat, coiled-coils, C-terminal RING zinc finger) and linked vacuolar function to organelle positioning and polarized growth in a fungal ortholog.\",\n      \"evidence\": \"Gene cloning, HA-tagging immunofluorescence, and nuclear migration mutant phenotyping in A. nidulans\",\n      \"pmids\": [\"11810240\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"RING domain function not biochemically tested\", \"Single fungal system, not validated in mammals\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Showed at the organismal level that vps18 loss disrupts endosomal-lysosomal trafficking and apical membrane delivery, producing tissue-specific liver pathology.\",\n      \"evidence\": \"Zebrafish insertional mutant histology and light microscopy of liver\",\n      \"pmids\": [\"16000385\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular trafficking step affected not pinpointed\", \"No cargo identified\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Connected VPS18/HOPS-mediated endolysosomal tethering to lysosome-related organelle biogenesis by demonstrating a requirement for melanosome maturation.\",\n      \"evidence\": \"Zebrafish insertional mutant with splicing analysis, EM of melanosomes, optokinetic assay\",\n      \"pmids\": [\"16827750\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct role in melanosome cargo delivery not resolved\", \"HOPS complex membership inferred, not biochemically shown here\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Demonstrated that VPS18 is required in engulfing cells for phagosome-lysosome fusion, extending its function beyond endosome biogenesis to corpse clearance.\",\n      \"evidence\": \"C. elegans deletion mutant analysis with fluorescence microscopy of phagosome-lysosome fusion and corpse accumulation\",\n      \"pmids\": [\"18923146\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Tethering versus fusion contribution not separated\", \"No physical partners mapped\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Implicated human VPS18 in viral assembly by showing it is needed for HIV-1 Gag plasma membrane targeting and infectious virion production.\",\n      \"evidence\": \"Yeast genetic screen plus siRNA knockdown of hVPS18 and VLP release assay in human cells\",\n      \"pmids\": [\"21450827\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct interaction with Gag not established\", \"Mechanism linking endolysosomal tethering to PM targeting unclear\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Established in mammals that VPS18 controls neuronal viability and migration by enabling multiple vesicle transport routes to the lysosome, acting upstream of β1 integrin and the degradation of Lysyl Oxidase.\",\n      \"evidence\": \"Conditional knockout mice with epistasis rescue (β1 integrin knockdown; Lox accumulation), Western blot, immunofluorescence, pathway assays\",\n      \"pmids\": [\"22854957\", \"22699122\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether VPS18 directly degrades these substrates or acts via general lysosomal failure not separated\", \"Cell-autonomous mechanism of migration regulation incomplete\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Resolved the molecular basis of HOPS assembly in humans, showing VPS18's RING domain directly recruits VPS41 via a zinc-dependent RING-RING heterodimer not conserved in yeast.\",\n      \"evidence\": \"In vitro co-purification of recombinant RING domains, cell co-IP, and domain truncation/mutagenesis\",\n      \"pmids\": [\"28931724\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Full HOPS subunit arrangement not solved structurally\", \"Functional consequence of the RING-RING interaction for tethering not directly tested\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Revealed a moonlighting E3 ubiquitin ligase activity for VPS18 that modulates signaling pathways, with PELP1 identified as a substrate restraining ERα activation.\",\n      \"evidence\": \"Overexpression and ubiquitination assays, co-IP, and Wnt/ERα/NF-κB signaling readouts\",\n      \"pmids\": [\"31015428\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Relies on overexpression; endogenous ligase activity not quantified\", \"Catalytic residues and substrate range not fully mapped\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Showed VPS18 stabilizes PD-L1 through endosomal interaction, glycosylation, and trans-Golgi recycling, defining a druggable axis linking VPS18 to antitumor immunity.\",\n      \"evidence\": \"Co-IP, VPS18 knockdown/knockout, Western blot for glycosylation/stability, pharmacological inhibition (RDN), in vivo tumor models\",\n      \"pmids\": [\"39413192\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct versus complex-mediated PD-L1 engagement unresolved\", \"Inhibitor selectivity for VPS18 not fully characterized\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Defined opposing roles in cancer and infection: VPS18 suppresses lung tumorigenesis via lysosomal degradation of EGFR, and protects against M. tuberculosis by maintaining phagosomal membrane integrity.\",\n      \"evidence\": \"Conditional KO in LSL-K-Ras mice with dnEGFR epistasis; genome-wide CRISPR screen with KO macrophage colocalization, integrity and bacterial growth assays\",\n      \"pmids\": [\"40615043\", \"39888996\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism by which VPS18 preserves phagosomal membrane integrity unknown\", \"Whether EGFR degradation is direct HOPS cargo handling or ligase-dependent not separated\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Linked VPS18 to human hematopoietic disease, showing its loss destabilizes HOPS/CORVET, blocks autophagic flux and neutrophil maturation, with a patient stop-gain mutation presenting as neutropenia.\",\n      \"evidence\": \"CRISPR Hoxb8 cells, iPSC differentiation, TEM, Western blot (LC3B-II, p62), zebrafish heterozygotes, patient mutation analysis\",\n      \"pmids\": [\"41526335\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Causality of the patient variant not formally proven by rescue\", \"Why neutrophil lineage is selectively vulnerable not explained\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How VPS18's tethering, RING-mediated assembly, and E3 ligase activities are coordinated at distinct membranes and which functions are direct versus secondary to general lysosomal failure remain unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structure of the assembled mammalian HOPS/CORVET complex\", \"Substrate spectrum of the ligase activity undefined\", \"Direct cargo recognition mechanisms for EGFR, PD-L1, and Lox not established\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0016874\", \"supporting_discovery_ids\": [9]},\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [9]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [8]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005768\", \"supporting_discovery_ids\": [4, 10]},\n      {\"term_id\": \"GO:0005764\", \"supporting_discovery_ids\": [0, 4]},\n      {\"term_id\": \"GO:0005773\", \"supporting_discovery_ids\": [0]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [1]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-5653656\", \"supporting_discovery_ids\": [0, 4, 6]},\n      {\"term_id\": \"R-HSA-9612973\", \"supporting_discovery_ids\": [6, 13]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [9, 12]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [10, 11]}\n    ],\n    \"complexes\": [\"HOPS\", \"CORVET\"],\n    \"partners\": [\"VPS41\", \"VPS11\", \"PELP1\", \"PD-L1\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}