{"gene":"VPS4B","run_date":"2026-06-11T09:02:06","timeline":{"discoveries":[{"year":2005,"finding":"The MIT domain of human VPS4B (SKD1) adopts an 'up-and-down' three-helix bundle structure, with a shallow crevice between helices A and C proposed as a protein-binding site for ESCRT-III interaction; a naturally occurring I58M SNP causes substantial thermal instability of the MIT domain.","method":"NMR solution structure determination; thermal stability assay of SNP mutant","journal":"Biochemical and biophysical research communications","confidence":"High","confidence_rationale":"Tier 1 / Moderate — NMR structure with functional SNP validation in a single focused study","pmids":["16018968"],"is_preprint":false},{"year":2004,"finding":"VPS4B (SKD1) interacts directly with SBP1 (a mammalian Vta1p homologue) via its C-terminal region (residues 198–309) and with mVps2/CHMP2A; ATPase activity of VPS4B regulates membrane association and assembly of a large hetero-oligomeric complex containing SBP1, implicating these interactions in endosomal/lysosomal membrane transport.","method":"Yeast two-hybrid screening; GST pull-down; dominant-negative ATPase-dead mutant SKD1(E235Q) overexpression; subcellular fractionation and localization","journal":"Journal of cell science","confidence":"High","confidence_rationale":"Tier 2 / Moderate — reciprocal yeast two-hybrid and GST pull-down with deletion mapping, dominant-negative functional analysis, single lab","pmids":["15173323"],"is_preprint":false},{"year":2005,"finding":"ALG-2, a Ca2+-binding penta-EF-hand protein, co-localizes with dominant-negative VPS4B(SKD1-E235Q) at aberrant endosomes in a Ca2+-dependent manner; a Ca2+-binding-defective ALG-2 mutant fails to co-localize, indicating Ca2+-dependent recruitment of ALG-2 to the ESCRT machinery at aberrant endosomes.","method":"Immunofluorescence microscopy with GFP-SKD1(E235Q) overexpression; Ca2+ chelation; Ca2+-binding-defective ALG-2 mutant","journal":"The Biochemical journal","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — localization experiments with genetic mutants, single lab, multiple orthogonal approaches (chelation + mutant)","pmids":["16004603"],"is_preprint":false},{"year":2007,"finding":"Dominant-negative forms of VPS4B (and VPS4A) inhibit HTLV-1 Gag budding, demonstrating that VPS4B-dependent ESCRT activity is required for retroviral budding via the MVB pathway.","method":"Dominant-negative VPS4B expression; virus-like particle release assay","journal":"Virology journal","confidence":"Medium","confidence_rationale":"Tier 3 / Weak — single Co-IP/dominant-negative approach, single lab, single method","pmids":["17601348"],"is_preprint":false},{"year":2012,"finding":"VPS4B regulates EGFR trafficking and abundance; loss of VPS4B function (shRNA knockdown or dominant-negative VPS4B-E235Q) leads to increased EGFR accumulation, altered intracellular compartmentalization, hyperactivation of EGFR signaling, and enhanced FOS/JUN/AP-1 activation in EGF-treated breast cancer cells.","method":"shRNA knockdown; dominant-negative VPS4B(E235Q) overexpression; immunofluorescence; Western blot; AP-1 reporter assay","journal":"Molecular and cellular biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — loss-of-function with defined molecular phenotype, multiple orthogonal methods, single lab","pmids":["22252323"],"is_preprint":false},{"year":2012,"finding":"VPS4B protein is degraded via the ubiquitin-proteasome system under hypoxic conditions, linking hypoxia to EGFR overproduction through VPS4B downregulation.","method":"Proteasome inhibitor treatment; hypoxia induction; Western blot","journal":"Molecular and cellular biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct biochemical demonstration of proteasomal degradation under hypoxia, single lab","pmids":["22252323"],"is_preprint":false},{"year":2016,"finding":"A splicing mutation (IVS7+46C>G) in VPS4B causes a 15-amino-acid insertion into the ATP-binding cassette, reduces VPS4B mRNA and protein expression, alters subcellular localization, and leads to dentin dysplasia type I; VPS4B acts as an upstream transducer of Wnt/β-catenin signaling to regulate odontogenesis, confirmed by zebrafish vps4b knockdown rescue with wild-type human VPS4B mRNA.","method":"Family-based genetic mapping; splice-site mutation identification; protein structure prediction; immunofluorescence localization; Wnt/β-catenin pathway analysis; zebrafish vps4b morpholino knockdown with mRNA rescue","journal":"Journal of medical genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — disease mutation with functional validation (localization, pathway, zebrafish rescue), single lab","pmids":["27247351"],"is_preprint":false},{"year":2020,"finding":"VPS4A and VPS4B are synthetic lethal paralogs: loss of VPS4B (adjacent to SMAD4 on 18q) renders cancer cells dependent on VPS4A; VPS4A suppression in VPS4B-deficient cells causes ESCRT-III filament accumulation, cytokinesis defects, nuclear deformation, G2/M arrest, and apoptosis, demonstrating that VPS4B participates in ESCRT-III disassembly required for abscission.","method":"CRISPR-SpCas9 and RNAi loss-of-function screens; genetic epistasis; immunofluorescence of ESCRT-III filaments; cell cycle analysis; tumor xenograft regression","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 2 / Strong — replicated across CRISPR and RNAi screens, multiple orthogonal cellular phenotype readouts, in vivo tumor model","pmids":["33326793"],"is_preprint":false},{"year":2020,"finding":"Combined depletion of VPS4A and VPS4B in colorectal cancer cells profoundly alters the cellular transcriptome and induces cell death accompanied by release of immunomodulatory molecules mediating inflammatory and anti-tumor responses, confirming synthetic lethality between the two paralogs.","method":"siRNA knockdown; transcriptome analysis; cell death assays; mouse xenograft models","journal":"EMBO molecular medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — loss-of-function with transcriptomic and in vivo validation, single lab","pmids":["31930723"],"is_preprint":false},{"year":2021,"finding":"Homozygous deletion of Vps4b in mice causes early embryonic lethality at ~E9.5, indicating an essential role for VPS4B in early embryonic development; VPS4B knockdown in IMR-32 cells dysregulates mRNA expression of apoptosis-, cell cycle-, and endocytosis-related genes.","method":"Vps4b conditional knockout mouse generation; timed embryo analysis; siRNA knockdown; qRT-PCR","journal":"Genesis (New York, N.Y. : 2000)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic KO with defined developmental phenotype, supported by in vitro loss-of-function, single lab","pmids":["33682352"],"is_preprint":false},{"year":2022,"finding":"VPS4B inactivation impairs autophagy, resulting in increased accumulation of CD8+ T cell-derived granzyme B and subsequent tumor cell lysis, placing VPS4B in the autophagic degradation pathway that controls susceptibility to cytotoxic T cell killing.","method":"In vitro and in vivo CRISPR screening; autophagy flux assays; granzyme B accumulation assay; orthotopic transplantation with CD8+ T cell readout","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Strong — CRISPR screen validated with mechanistic follow-up (autophagy assay, granzyme B), in vivo confirmation, single lab with multiple methods","pmids":["35379808"],"is_preprint":false},{"year":2024,"finding":"VPS4B regulates the dynamics (recycling/disassembly) of ESCRT-III during nuclear envelope (NE) repair; insufficient VPS4B expression leads to inadequate response to mechanical NE stress and defective NE repair in glioblastoma cells.","method":"VPS4B knockdown/expression comparison; nuclear deformation and DNA damage readouts under mechanical NE stress; ESCRT-III dynamics imaging","journal":"Nucleus (Austin, Tex.)","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — loss-of-function with defined cellular phenotype, single lab, limited methods described in abstract","pmids":["39540606"],"is_preprint":false},{"year":2012,"finding":"Both wild-type VPS4B and its dominant-negative mutant VPS4B-K180Q suppress HBV replication in vivo, reducing serum HBsAg, HBeAg, and HBV-DNA levels and intrahepatic HBV DNA and mRNA; the DN mutant showed more potent anti-HBV effect than wild-type VPS4B.","method":"Hydrodynamic tail-vein injection of VPS4B and HBV vectors into mice; ECL quantification of HBsAg/HBeAg; real-time PCR for HBV DNA; Southern blot; immunohistochemistry","journal":"Journal of Huazhong University of Science and Technology. Medical sciences","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single in vivo study, mechanism of anti-HBV action not resolved, single lab","pmids":["22684550"],"is_preprint":false},{"year":2023,"finding":"Downregulated VPS4B expression in venous malformation endothelial cells, caused by abnormally activated AKT signaling (which suppresses VPS4B), leads to increased size of small extracellular vesicles (sEVs); inhibiting AKT corrects sEV size by restoring VPS4B expression, placing VPS4B downstream of p-AKT in sEV biogenesis.","method":"Western blot; nanoparticle tracking analysis; siRNA knockdown of VPS4B; AKT inhibitor treatment; immunohistochemistry","journal":"Oral diseases","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, pathway inference from inhibitor/siRNA, mechanism connecting AKT to VPS4B not directly demonstrated","pmids":["37154262"],"is_preprint":false},{"year":2025,"finding":"VPS4B triggers lipid droplet release from adipocytes by interacting with ANXA5 (annexin A5); O-GlcNAc modification of VPS4B (enhanced via inhibition of the STK11/LKB1-AMPK pathway and activation of the hexosamine biosynthesis pathway) increases this activity.","method":"Co-culture system; RNA-seq and proteomics; co-IP (VPS4B–ANXA5 interaction); siRNA knockdown; in vivo tumor models","journal":"Cancer & metabolism","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, interaction identified but limited mechanistic resolution in abstract","pmids":["40410860"],"is_preprint":false}],"current_model":"VPS4B is an AAA-ATPase that uses its MIT domain (three-helix bundle) to engage ESCRT-III subunits (including CHMP2A/mVps2), driving ATP-dependent disassembly and recycling of ESCRT-III filaments at multivesicular body endosomes, the nuclear envelope, and the cytokinetic midbody; it is regulated by SBP1 (Vta1p homologue), targeted for proteasomal degradation under hypoxia, and is functionally redundant with its paralog VPS4A—loss of either alone is tolerated, but combined loss causes ESCRT-III accumulation, cytokinesis failure, and apoptosis; VPS4B also controls EGFR trafficking/degradation, autophagy flux (limiting granzyme B accumulation), and sEV size, and its ATPase activity is required for retroviral budding and normal embryonic development."},"narrative":{"mechanistic_narrative":"VPS4B is an AAA-ATPase that drives the ATP-dependent disassembly and recycling of ESCRT-III filaments, a function central to multiple membrane-remodeling events including cytokinetic abscission and nuclear envelope repair [PMID:33326793, PMID:39540606]. Its N-terminal MIT domain adopts an up-and-down three-helix bundle that presents a crevice between helices A and C for engaging ESCRT-III subunits, and a natural I58M variant destabilizes this fold [PMID:16018968]. Through its C-terminal region VPS4B binds the Vta1p homologue SBP1 and the ESCRT-III subunit mVps2/CHMP2A, and its ATPase activity governs membrane association and assembly of a large SBP1-containing hetero-oligomeric complex required for endosomal/lysosomal transport [PMID:15173323]; recruitment of the Ca2+-binding protein ALG-2 to ESCRT-decorated endosomes is Ca2+-dependent [PMID:16004603]. VPS4B and its paralog VPS4A are synthetic-lethal: loss of either alone is tolerated, but co-depletion causes ESCRT-III filament accumulation, cytokinesis failure, nuclear deformation, G2/M arrest, and apoptosis, with attendant release of immunomodulatory molecules [PMID:33326793, PMID:31930723]. Beyond ESCRT-III turnover, VPS4B controls EGFR trafficking and degradation—its loss causing EGFR accumulation and hyperactivated EGFR/AP-1 signaling—and is itself targeted for proteasomal degradation under hypoxia, coupling oxygen status to receptor abundance [PMID:22252323]. VPS4B further supports autophagic flux that limits granzyme B accumulation and tumor-cell susceptibility to cytotoxic T cells [PMID:35379808], and its ATPase activity is required for retroviral (HTLV-1 Gag) budding [PMID:17601348] and for early embryonic development, with homozygous knockout causing lethality around E9.5 [PMID:33682352]. A splicing mutation reducing VPS4B expression and mislocalizing the protein causes dentin dysplasia type I, with VPS4B acting upstream of Wnt/β-catenin signaling in odontogenesis [PMID:27247351].","teleology":[{"year":2004,"claim":"Established that VPS4B physically engages the ESCRT machinery and that its ATPase activity governs assembly of a membrane-associated regulatory complex, defining its biochemical role in endosomal transport.","evidence":"Yeast two-hybrid, GST pull-down with deletion mapping, and dominant-negative E235Q overexpression with fractionation","pmids":["15173323"],"confidence":"High","gaps":["Did not resolve the structural basis of ESCRT-III recognition","Stoichiometry and architecture of the SBP1-containing complex not determined"]},{"year":2005,"claim":"Defined the structural module by which VPS4B docks onto ESCRT-III, showing the MIT domain is a three-helix bundle with a candidate binding crevice and that a natural SNP destabilizes it.","evidence":"NMR solution structure and thermal stability assay of the I58M variant","pmids":["16018968"],"confidence":"High","gaps":["No co-structure with an ESCRT-III partner","Functional consequence of I58M instability in cells untested"]},{"year":2005,"claim":"Showed that recruitment of regulatory factors to VPS4B-marked endosomes is calcium-gated, linking Ca2+ signaling to ESCRT machinery localization.","evidence":"Immunofluorescence with GFP-SKD1(E235Q), Ca2+ chelation, and Ca2+-binding-defective ALG-2 mutant","pmids":["16004603"],"confidence":"Medium","gaps":["Whether ALG-2 binds VPS4B directly versus other ESCRT components unresolved","Functional output of Ca2+-dependent recruitment not established"]},{"year":2007,"claim":"Demonstrated that VPS4B-dependent ESCRT activity is co-opted for retroviral budding, generalizing its membrane-scission role to viral egress.","evidence":"Dominant-negative VPS4B expression and HTLV-1 Gag virus-like particle release assay","pmids":["17601348"],"confidence":"Medium","gaps":["Single dominant-negative readout without endogenous loss-of-function","Direct VPS4B–Gag/ESCRT contacts not mapped"]},{"year":2012,"claim":"Connected VPS4B function to receptor signaling control and to hypoxic regulation, showing VPS4B limits EGFR abundance and is destabilized under low oxygen.","evidence":"shRNA knockdown, dominant-negative E235Q, AP-1 reporter, and proteasome-inhibitor/hypoxia Western blots in breast cancer cells","pmids":["22252323"],"confidence":"Medium","gaps":["E3 ligase mediating hypoxic degradation not identified","Whether EGFR effects are direct trafficking or downstream of broader ESCRT failure unclear"]},{"year":2016,"claim":"Linked VPS4B to a Mendelian disease and a developmental signaling axis, establishing VPS4B as an upstream regulator of Wnt/β-catenin in tooth development.","evidence":"Family-based mapping of a splice mutation, localization, pathway analysis, and zebrafish morpholino rescue with human VPS4B mRNA","pmids":["27247351"],"confidence":"Medium","gaps":["Molecular link between ESCRT activity and Wnt signaling not defined","Tissue-specificity of the dentin phenotype unexplained"]},{"year":2020,"claim":"Resolved the paralog relationship, showing VPS4A and VPS4B are synthetic-lethal and that VPS4B participates in ESCRT-III disassembly required for abscission, with therapeutic implications for VPS4B-deleted cancers.","evidence":"CRISPR and RNAi screens, genetic epistasis, ESCRT-III imaging, cell-cycle analysis, transcriptomics, and xenograft models across two studies","pmids":["33326793","31930723"],"confidence":"High","gaps":["Degree of mechanistic non-redundancy between paralogs not fully dissected","Basis of the immunomodulatory release upon co-depletion unresolved"]},{"year":2021,"claim":"Established that VPS4B is individually essential in vivo despite paralog redundancy in culture, with knockout causing early embryonic lethality.","evidence":"Vps4b conditional knockout mice with timed embryo analysis and siRNA knockdown with qRT-PCR","pmids":["33682352"],"confidence":"Medium","gaps":["Cause of E9.5 lethality not mechanistically resolved","Tissue-specific requirements not dissected"]},{"year":2022,"claim":"Placed VPS4B in the autophagic degradation pathway controlling immune killing, showing its loss impairs autophagy and allows granzyme B accumulation that sensitizes tumor cells to CD8+ T cells.","evidence":"In vitro and in vivo CRISPR screens, autophagy flux assays, granzyme B accumulation, and orthotopic transplantation","pmids":["35379808"],"confidence":"High","gaps":["Step in autophagy requiring VPS4B not pinpointed","Whether granzyme B clearance is direct autophagic substrate handling unclear"]},{"year":2024,"claim":"Extended VPS4B's ESCRT-III recycling role to nuclear envelope repair, showing insufficient VPS4B impairs response to mechanical NE stress.","evidence":"VPS4B knockdown/expression comparison with nuclear deformation, DNA damage, and ESCRT-III dynamics imaging in glioblastoma cells","pmids":["39540606"],"confidence":"Medium","gaps":["Limited methodology described","Quantitative contribution relative to VPS4A at the NE not established"]},{"year":2025,"claim":"Implicated VPS4B in adipocyte lipid droplet release through an ANXA5 interaction modulated by O-GlcNAcylation, suggesting metabolic regulation of VPS4B activity.","evidence":"Co-culture, RNA-seq/proteomics, co-IP of VPS4B–ANXA5, siRNA knockdown, and in vivo tumor models","pmids":["40410860"],"confidence":"Low","gaps":["Single-lab interaction with limited mechanistic resolution","Site and functional impact of O-GlcNAc modification not mapped","Reciprocal validation of VPS4B–ANXA5 binding not shown"]},{"year":null,"claim":"It remains unknown how VPS4B's single ESCRT-III disassembly activity is differentially deployed and regulated across its distinct membrane contexts (endosomes, midbody, nuclear envelope) and how this connects mechanistically to downstream signaling outcomes such as Wnt and EGFR pathways.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structural model of the active VPS4B–ESCRT-III–cofactor assembly in human cells","Determinants of context-specific recruitment unidentified","Direct link between membrane-scission activity and transcriptional/signaling phenotypes unresolved"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140657","term_label":"ATP-dependent activity","supporting_discovery_ids":[1,7]},{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[1,7]},{"term_id":"GO:0008092","term_label":"cytoskeletal protein binding","supporting_discovery_ids":[0,1]}],"localization":[{"term_id":"GO:0005768","term_label":"endosome","supporting_discovery_ids":[1,2,4]},{"term_id":"GO:0005635","term_label":"nuclear envelope","supporting_discovery_ids":[11]},{"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":[1,4,3]},{"term_id":"R-HSA-1640170","term_label":"Cell Cycle","supporting_discovery_ids":[7]},{"term_id":"R-HSA-9612973","term_label":"Autophagy","supporting_discovery_ids":[10]}],"complexes":["ESCRT-III"],"partners":["CHMP2A","SBP1","ALG-2","ANXA5","VPS4A"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"O75351","full_name":"Vacuolar protein sorting-associated protein 4B","aliases":["Cell migration-inducing gene 1 protein","Suppressor of K(+) transport growth defect 1","Protein SKD1"],"length_aa":444,"mass_kda":49.3,"function":"Involved in late steps of the endosomal multivesicular bodies (MVB) pathway. Recognizes membrane-associated ESCRT-III assemblies and catalyzes their ATP-dependent disassembly, possibly in combination with membrane fission (PubMed:18687924). Redistributes the ESCRT-III components to the cytoplasm for further rounds of MVB sorting. MVBs contain intraluminal vesicles (ILVs) that are generated by invagination and scission from the limiting membrane of the endosome and mostly are delivered to lysosomes enabling degradation of membrane proteins, such as stimulated growth factor receptors, lysosomal enzymes and lipids. VPS4A/B are required for the exosomal release of SDCBP, CD63 and syndecan (PubMed:22660413) (Microbial infection) In conjunction with the ESCRT machinery also appears to function in topologically equivalent membrane fission events, such as the terminal stages of cytokinesis and enveloped virus budding (HIV-1 and other lentiviruses)","subcellular_location":"Late endosome membrane","url":"https://www.uniprot.org/uniprotkb/O75351/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/VPS4B","classification":"Not Classified","n_dependent_lines":161,"n_total_lines":1208,"dependency_fraction":0.13327814569536423},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/VPS4B","total_profiled":1310},"omim":[{"mim_id":"621440","title":"DENTIN DYSPLASIA, TYPE IB; DTDP1B","url":"https://www.omim.org/entry/621440"},{"mim_id":"616434","title":"IST1 FACTOR ASSOCIATED WITH ESCRT-III; IST1","url":"https://www.omim.org/entry/616434"},{"mim_id":"610902","title":"VESSICLE TRAFFICKING 1; VTA1","url":"https://www.omim.org/entry/610902"},{"mim_id":"610897","title":"CHARGED MULTIVESICULAR BODY PROTEIN 4B; CHMP4B","url":"https://www.omim.org/entry/610897"},{"mim_id":"610893","title":"CHARGED MULTIVESICULAR BODY PROTEIN 2A; CHMP2A","url":"https://www.omim.org/entry/610893"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Vesicles","reliability":"Approved"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/VPS4B"},"hgnc":{"alias_symbol":["VPS4-2","SKD1B"],"prev_symbol":["SKD1"]},"alphafold":{"accession":"O75351","domains":[{"cath_id":"1.20.58.80","chopping":"5-77","consensus_level":"high","plddt":88.7603,"start":5,"end":77},{"cath_id":"3.40.50.300","chopping":"123-296","consensus_level":"high","plddt":87.6983,"start":123,"end":296},{"cath_id":"1.10.8.60","chopping":"302-422","consensus_level":"high","plddt":95.9935,"start":302,"end":422}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/O75351","model_url":"https://alphafold.ebi.ac.uk/files/AF-O75351-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-O75351-F1-predicted_aligned_error_v6.png","plddt_mean":85.94},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=VPS4B","jax_strain_url":"https://www.jax.org/strain/search?query=VPS4B"},"sequence":{"accession":"O75351","fasta_url":"https://rest.uniprot.org/uniprotkb/O75351.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/O75351/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/O75351"}},"corpus_meta":[{"pmid":"16004603","id":"PMC_16004603","title":"The penta-EF-hand protein ALG-2 interacts directly with the ESCRT-I component TSG101, and Ca2+-dependently co-localizes to aberrant endosomes with dominant-negative AAA ATPase SKD1/Vps4B.","date":"2005","source":"The Biochemical journal","url":"https://pubmed.ncbi.nlm.nih.gov/16004603","citation_count":69,"is_preprint":false},{"pmid":"33326793","id":"PMC_33326793","title":"Synthetic Lethal Interaction between the ESCRT Paralog Enzymes VPS4A and VPS4B in Cancers Harboring Loss of Chromosome 18q or 16q.","date":"2020","source":"Cell reports","url":"https://pubmed.ncbi.nlm.nih.gov/33326793","citation_count":48,"is_preprint":false},{"pmid":"15173323","id":"PMC_15173323","title":"Mammalian class E Vps proteins, SBP1 and mVps2/CHMP2A, interact with and regulate the function of an AAA-ATPase SKD1/Vps4B.","date":"2004","source":"Journal of cell science","url":"https://pubmed.ncbi.nlm.nih.gov/15173323","citation_count":43,"is_preprint":false},{"pmid":"35379808","id":"PMC_35379808","title":"Loss of Rnf31 and Vps4b sensitizes pancreatic cancer to T cell-mediated killing.","date":"2022","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/35379808","citation_count":41,"is_preprint":false},{"pmid":"31930723","id":"PMC_31930723","title":"Synthetic lethality between VPS4A and VPS4B triggers an inflammatory response in colorectal cancer.","date":"2020","source":"EMBO molecular medicine","url":"https://pubmed.ncbi.nlm.nih.gov/31930723","citation_count":41,"is_preprint":false},{"pmid":"22252323","id":"PMC_22252323","title":"Identification of an AAA ATPase VPS4B-dependent pathway that modulates epidermal growth factor receptor abundance and signaling during hypoxia.","date":"2012","source":"Molecular and cellular biology","url":"https://pubmed.ncbi.nlm.nih.gov/22252323","citation_count":34,"is_preprint":false},{"pmid":"16018968","id":"PMC_16018968","title":"Structural characterization of the MIT domain from human Vps4b.","date":"2005","source":"Biochemical and 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neurobiology","url":"https://pubmed.ncbi.nlm.nih.gov/24077878","citation_count":15,"is_preprint":false},{"pmid":"28744712","id":"PMC_28744712","title":"Vacuolar Protein Sorting 4B (VPS4B) Regulates Apoptosis of Chondrocytes via p38 Mitogen-Activated Protein Kinases (MAPK) in Osteoarthritis.","date":"2017","source":"Inflammation","url":"https://pubmed.ncbi.nlm.nih.gov/28744712","citation_count":14,"is_preprint":false},{"pmid":"33442254","id":"PMC_33442254","title":"MicroRNA-488-3p Regulates Neuronal Cell Death in Cerebral Ischemic Stroke Through Vacuolar Protein Sorting 4B (VPS4B).","date":"2021","source":"Neuropsychiatric disease and treatment","url":"https://pubmed.ncbi.nlm.nih.gov/33442254","citation_count":11,"is_preprint":false},{"pmid":"23431444","id":"PMC_23431444","title":"An Internal Standard-Assisted Synthesis and Degradation Proteomic Approach Reveals the Potential Linkage between VPS4B Depletion and Activation of Fatty Acid β-Oxidation in Breast Cancer 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I.","date":"2020","source":"International journal of oral science","url":"https://pubmed.ncbi.nlm.nih.gov/32737282","citation_count":5,"is_preprint":false},{"pmid":"30634912","id":"PMC_30634912","title":"Vps4b heterozygous mice do not develop tooth defects that replicate human dentin dysplasia I.","date":"2019","source":"BMC genetics","url":"https://pubmed.ncbi.nlm.nih.gov/30634912","citation_count":4,"is_preprint":false},{"pmid":"37154262","id":"PMC_37154262","title":"p-AKT/VPS4B regulates the small extracellular vesicle size in venous malformation endothelial cells.","date":"2023","source":"Oral diseases","url":"https://pubmed.ncbi.nlm.nih.gov/37154262","citation_count":2,"is_preprint":false},{"pmid":"39540606","id":"PMC_39540606","title":"VPS4B orchestrates response to nuclear envelope stress by regulating ESCRT-III dynamics in glioblastoma.","date":"2024","source":"Nucleus (Austin, Tex.)","url":"https://pubmed.ncbi.nlm.nih.gov/39540606","citation_count":2,"is_preprint":false},{"pmid":"40410860","id":"PMC_40410860","title":"Improved VPS4B O-GlcNAc modification triggers lipid droplets transferring from adipocytes to nasopharyngeal carcinoma cells.","date":"2025","source":"Cancer & metabolism","url":"https://pubmed.ncbi.nlm.nih.gov/40410860","citation_count":1,"is_preprint":false},{"pmid":"22684550","id":"PMC_22684550","title":"Inhibition of HBV replication by VPS4B and its dominant negative mutant VPS4B-K180Q in vivo.","date":"2012","source":"Journal of Huazhong University of Science and Technology. Medical sciences = Hua zhong ke ji da xue xue bao. Yi xue Ying De wen ban = Huazhong keji daxue xuebao. Yixue Yingdewen ban","url":"https://pubmed.ncbi.nlm.nih.gov/22684550","citation_count":1,"is_preprint":false},{"pmid":"31218856","id":"PMC_31218856","title":"[Spatio-temporal expression of dentin sialophosphoprotein and collagen Ⅰ during molar tooth germ development in vps4b knockout mouse].","date":"2019","source":"Hua xi kou qiang yi xue za zhi = Huaxi kouqiang yixue zazhi = West China journal of stomatology","url":"https://pubmed.ncbi.nlm.nih.gov/31218856","citation_count":1,"is_preprint":false},{"pmid":"34041875","id":"PMC_34041875","title":"Expressions of cytokeratin 14 and proliferating cell nuclear antigen in the Hertwig's epithelial root sheath of a Vps4b knockout mouse.","date":"2021","source":"Hua xi kou qiang yi xue za zhi = Huaxi kouqiang yixue zazhi = West China journal of stomatology","url":"https://pubmed.ncbi.nlm.nih.gov/34041875","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":14163,"output_tokens":3667,"usd":0.048747,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":11361,"output_tokens":3972,"usd":0.078052,"stage2_stop_reason":"end_turn"},"total_usd":0.126799,"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\": 2005,\n      \"finding\": \"The MIT domain of human VPS4B (SKD1) adopts an 'up-and-down' three-helix bundle structure, with a shallow crevice between helices A and C proposed as a protein-binding site for ESCRT-III interaction; a naturally occurring I58M SNP causes substantial thermal instability of the MIT domain.\",\n      \"method\": \"NMR solution structure determination; thermal stability assay of SNP mutant\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — NMR structure with functional SNP validation in a single focused study\",\n      \"pmids\": [\"16018968\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"VPS4B (SKD1) interacts directly with SBP1 (a mammalian Vta1p homologue) via its C-terminal region (residues 198–309) and with mVps2/CHMP2A; ATPase activity of VPS4B regulates membrane association and assembly of a large hetero-oligomeric complex containing SBP1, implicating these interactions in endosomal/lysosomal membrane transport.\",\n      \"method\": \"Yeast two-hybrid screening; GST pull-down; dominant-negative ATPase-dead mutant SKD1(E235Q) overexpression; subcellular fractionation and localization\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal yeast two-hybrid and GST pull-down with deletion mapping, dominant-negative functional analysis, single lab\",\n      \"pmids\": [\"15173323\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"ALG-2, a Ca2+-binding penta-EF-hand protein, co-localizes with dominant-negative VPS4B(SKD1-E235Q) at aberrant endosomes in a Ca2+-dependent manner; a Ca2+-binding-defective ALG-2 mutant fails to co-localize, indicating Ca2+-dependent recruitment of ALG-2 to the ESCRT machinery at aberrant endosomes.\",\n      \"method\": \"Immunofluorescence microscopy with GFP-SKD1(E235Q) overexpression; Ca2+ chelation; Ca2+-binding-defective ALG-2 mutant\",\n      \"journal\": \"The Biochemical journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — localization experiments with genetic mutants, single lab, multiple orthogonal approaches (chelation + mutant)\",\n      \"pmids\": [\"16004603\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"Dominant-negative forms of VPS4B (and VPS4A) inhibit HTLV-1 Gag budding, demonstrating that VPS4B-dependent ESCRT activity is required for retroviral budding via the MVB pathway.\",\n      \"method\": \"Dominant-negative VPS4B expression; virus-like particle release assay\",\n      \"journal\": \"Virology journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single Co-IP/dominant-negative approach, single lab, single method\",\n      \"pmids\": [\"17601348\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"VPS4B regulates EGFR trafficking and abundance; loss of VPS4B function (shRNA knockdown or dominant-negative VPS4B-E235Q) leads to increased EGFR accumulation, altered intracellular compartmentalization, hyperactivation of EGFR signaling, and enhanced FOS/JUN/AP-1 activation in EGF-treated breast cancer cells.\",\n      \"method\": \"shRNA knockdown; dominant-negative VPS4B(E235Q) overexpression; immunofluorescence; Western blot; AP-1 reporter assay\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — loss-of-function with defined molecular phenotype, multiple orthogonal methods, single lab\",\n      \"pmids\": [\"22252323\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"VPS4B protein is degraded via the ubiquitin-proteasome system under hypoxic conditions, linking hypoxia to EGFR overproduction through VPS4B downregulation.\",\n      \"method\": \"Proteasome inhibitor treatment; hypoxia induction; Western blot\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct biochemical demonstration of proteasomal degradation under hypoxia, single lab\",\n      \"pmids\": [\"22252323\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"A splicing mutation (IVS7+46C>G) in VPS4B causes a 15-amino-acid insertion into the ATP-binding cassette, reduces VPS4B mRNA and protein expression, alters subcellular localization, and leads to dentin dysplasia type I; VPS4B acts as an upstream transducer of Wnt/β-catenin signaling to regulate odontogenesis, confirmed by zebrafish vps4b knockdown rescue with wild-type human VPS4B mRNA.\",\n      \"method\": \"Family-based genetic mapping; splice-site mutation identification; protein structure prediction; immunofluorescence localization; Wnt/β-catenin pathway analysis; zebrafish vps4b morpholino knockdown with mRNA rescue\",\n      \"journal\": \"Journal of medical genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — disease mutation with functional validation (localization, pathway, zebrafish rescue), single lab\",\n      \"pmids\": [\"27247351\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"VPS4A and VPS4B are synthetic lethal paralogs: loss of VPS4B (adjacent to SMAD4 on 18q) renders cancer cells dependent on VPS4A; VPS4A suppression in VPS4B-deficient cells causes ESCRT-III filament accumulation, cytokinesis defects, nuclear deformation, G2/M arrest, and apoptosis, demonstrating that VPS4B participates in ESCRT-III disassembly required for abscission.\",\n      \"method\": \"CRISPR-SpCas9 and RNAi loss-of-function screens; genetic epistasis; immunofluorescence of ESCRT-III filaments; cell cycle analysis; tumor xenograft regression\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — replicated across CRISPR and RNAi screens, multiple orthogonal cellular phenotype readouts, in vivo tumor model\",\n      \"pmids\": [\"33326793\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Combined depletion of VPS4A and VPS4B in colorectal cancer cells profoundly alters the cellular transcriptome and induces cell death accompanied by release of immunomodulatory molecules mediating inflammatory and anti-tumor responses, confirming synthetic lethality between the two paralogs.\",\n      \"method\": \"siRNA knockdown; transcriptome analysis; cell death assays; mouse xenograft models\",\n      \"journal\": \"EMBO molecular medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — loss-of-function with transcriptomic and in vivo validation, single lab\",\n      \"pmids\": [\"31930723\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Homozygous deletion of Vps4b in mice causes early embryonic lethality at ~E9.5, indicating an essential role for VPS4B in early embryonic development; VPS4B knockdown in IMR-32 cells dysregulates mRNA expression of apoptosis-, cell cycle-, and endocytosis-related genes.\",\n      \"method\": \"Vps4b conditional knockout mouse generation; timed embryo analysis; siRNA knockdown; qRT-PCR\",\n      \"journal\": \"Genesis (New York, N.Y. : 2000)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic KO with defined developmental phenotype, supported by in vitro loss-of-function, single lab\",\n      \"pmids\": [\"33682352\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"VPS4B inactivation impairs autophagy, resulting in increased accumulation of CD8+ T cell-derived granzyme B and subsequent tumor cell lysis, placing VPS4B in the autophagic degradation pathway that controls susceptibility to cytotoxic T cell killing.\",\n      \"method\": \"In vitro and in vivo CRISPR screening; autophagy flux assays; granzyme B accumulation assay; orthotopic transplantation with CD8+ T cell readout\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — CRISPR screen validated with mechanistic follow-up (autophagy assay, granzyme B), in vivo confirmation, single lab with multiple methods\",\n      \"pmids\": [\"35379808\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"VPS4B regulates the dynamics (recycling/disassembly) of ESCRT-III during nuclear envelope (NE) repair; insufficient VPS4B expression leads to inadequate response to mechanical NE stress and defective NE repair in glioblastoma cells.\",\n      \"method\": \"VPS4B knockdown/expression comparison; nuclear deformation and DNA damage readouts under mechanical NE stress; ESCRT-III dynamics imaging\",\n      \"journal\": \"Nucleus (Austin, Tex.)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — loss-of-function with defined cellular phenotype, single lab, limited methods described in abstract\",\n      \"pmids\": [\"39540606\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Both wild-type VPS4B and its dominant-negative mutant VPS4B-K180Q suppress HBV replication in vivo, reducing serum HBsAg, HBeAg, and HBV-DNA levels and intrahepatic HBV DNA and mRNA; the DN mutant showed more potent anti-HBV effect than wild-type VPS4B.\",\n      \"method\": \"Hydrodynamic tail-vein injection of VPS4B and HBV vectors into mice; ECL quantification of HBsAg/HBeAg; real-time PCR for HBV DNA; Southern blot; immunohistochemistry\",\n      \"journal\": \"Journal of Huazhong University of Science and Technology. Medical sciences\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single in vivo study, mechanism of anti-HBV action not resolved, single lab\",\n      \"pmids\": [\"22684550\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Downregulated VPS4B expression in venous malformation endothelial cells, caused by abnormally activated AKT signaling (which suppresses VPS4B), leads to increased size of small extracellular vesicles (sEVs); inhibiting AKT corrects sEV size by restoring VPS4B expression, placing VPS4B downstream of p-AKT in sEV biogenesis.\",\n      \"method\": \"Western blot; nanoparticle tracking analysis; siRNA knockdown of VPS4B; AKT inhibitor treatment; immunohistochemistry\",\n      \"journal\": \"Oral diseases\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, pathway inference from inhibitor/siRNA, mechanism connecting AKT to VPS4B not directly demonstrated\",\n      \"pmids\": [\"37154262\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"VPS4B triggers lipid droplet release from adipocytes by interacting with ANXA5 (annexin A5); O-GlcNAc modification of VPS4B (enhanced via inhibition of the STK11/LKB1-AMPK pathway and activation of the hexosamine biosynthesis pathway) increases this activity.\",\n      \"method\": \"Co-culture system; RNA-seq and proteomics; co-IP (VPS4B–ANXA5 interaction); siRNA knockdown; in vivo tumor models\",\n      \"journal\": \"Cancer & metabolism\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, interaction identified but limited mechanistic resolution in abstract\",\n      \"pmids\": [\"40410860\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"VPS4B is an AAA-ATPase that uses its MIT domain (three-helix bundle) to engage ESCRT-III subunits (including CHMP2A/mVps2), driving ATP-dependent disassembly and recycling of ESCRT-III filaments at multivesicular body endosomes, the nuclear envelope, and the cytokinetic midbody; it is regulated by SBP1 (Vta1p homologue), targeted for proteasomal degradation under hypoxia, and is functionally redundant with its paralog VPS4A—loss of either alone is tolerated, but combined loss causes ESCRT-III accumulation, cytokinesis failure, and apoptosis; VPS4B also controls EGFR trafficking/degradation, autophagy flux (limiting granzyme B accumulation), and sEV size, and its ATPase activity is required for retroviral budding and normal embryonic development.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"VPS4B is an AAA-ATPase that drives the ATP-dependent disassembly and recycling of ESCRT-III filaments, a function central to multiple membrane-remodeling events including cytokinetic abscission and nuclear envelope repair [#7, #11]. Its N-terminal MIT domain adopts an up-and-down three-helix bundle that presents a crevice between helices A and C for engaging ESCRT-III subunits, and a natural I58M variant destabilizes this fold [#0]. Through its C-terminal region VPS4B binds the Vta1p homologue SBP1 and the ESCRT-III subunit mVps2/CHMP2A, and its ATPase activity governs membrane association and assembly of a large SBP1-containing hetero-oligomeric complex required for endosomal/lysosomal transport [#1]; recruitment of the Ca2+-binding protein ALG-2 to ESCRT-decorated endosomes is Ca2+-dependent [#2]. VPS4B and its paralog VPS4A are synthetic-lethal: loss of either alone is tolerated, but co-depletion causes ESCRT-III filament accumulation, cytokinesis failure, nuclear deformation, G2/M arrest, and apoptosis, with attendant release of immunomodulatory molecules [#7, #8]. Beyond ESCRT-III turnover, VPS4B controls EGFR trafficking and degradation—its loss causing EGFR accumulation and hyperactivated EGFR/AP-1 signaling—and is itself targeted for proteasomal degradation under hypoxia, coupling oxygen status to receptor abundance [#4, #5]. VPS4B further supports autophagic flux that limits granzyme B accumulation and tumor-cell susceptibility to cytotoxic T cells [#10], and its ATPase activity is required for retroviral (HTLV-1 Gag) budding [#3] and for early embryonic development, with homozygous knockout causing lethality around E9.5 [#9]. A splicing mutation reducing VPS4B expression and mislocalizing the protein causes dentin dysplasia type I, with VPS4B acting upstream of Wnt/\\u03b2-catenin signaling in odontogenesis [#6].\",\n  \"teleology\": [\n    {\n      \"year\": 2004,\n      \"claim\": \"Established that VPS4B physically engages the ESCRT machinery and that its ATPase activity governs assembly of a membrane-associated regulatory complex, defining its biochemical role in endosomal transport.\",\n      \"evidence\": \"Yeast two-hybrid, GST pull-down with deletion mapping, and dominant-negative E235Q overexpression with fractionation\",\n      \"pmids\": [\"15173323\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not resolve the structural basis of ESCRT-III recognition\", \"Stoichiometry and architecture of the SBP1-containing complex not determined\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Defined the structural module by which VPS4B docks onto ESCRT-III, showing the MIT domain is a three-helix bundle with a candidate binding crevice and that a natural SNP destabilizes it.\",\n      \"evidence\": \"NMR solution structure and thermal stability assay of the I58M variant\",\n      \"pmids\": [\"16018968\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No co-structure with an ESCRT-III partner\", \"Functional consequence of I58M instability in cells untested\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Showed that recruitment of regulatory factors to VPS4B-marked endosomes is calcium-gated, linking Ca2+ signaling to ESCRT machinery localization.\",\n      \"evidence\": \"Immunofluorescence with GFP-SKD1(E235Q), Ca2+ chelation, and Ca2+-binding-defective ALG-2 mutant\",\n      \"pmids\": [\"16004603\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether ALG-2 binds VPS4B directly versus other ESCRT components unresolved\", \"Functional output of Ca2+-dependent recruitment not established\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Demonstrated that VPS4B-dependent ESCRT activity is co-opted for retroviral budding, generalizing its membrane-scission role to viral egress.\",\n      \"evidence\": \"Dominant-negative VPS4B expression and HTLV-1 Gag virus-like particle release assay\",\n      \"pmids\": [\"17601348\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single dominant-negative readout without endogenous loss-of-function\", \"Direct VPS4B–Gag/ESCRT contacts not mapped\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Connected VPS4B function to receptor signaling control and to hypoxic regulation, showing VPS4B limits EGFR abundance and is destabilized under low oxygen.\",\n      \"evidence\": \"shRNA knockdown, dominant-negative E235Q, AP-1 reporter, and proteasome-inhibitor/hypoxia Western blots in breast cancer cells\",\n      \"pmids\": [\"22252323\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"E3 ligase mediating hypoxic degradation not identified\", \"Whether EGFR effects are direct trafficking or downstream of broader ESCRT failure unclear\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Linked VPS4B to a Mendelian disease and a developmental signaling axis, establishing VPS4B as an upstream regulator of Wnt/\\u03b2-catenin in tooth development.\",\n      \"evidence\": \"Family-based mapping of a splice mutation, localization, pathway analysis, and zebrafish morpholino rescue with human VPS4B mRNA\",\n      \"pmids\": [\"27247351\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular link between ESCRT activity and Wnt signaling not defined\", \"Tissue-specificity of the dentin phenotype unexplained\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Resolved the paralog relationship, showing VPS4A and VPS4B are synthetic-lethal and that VPS4B participates in ESCRT-III disassembly required for abscission, with therapeutic implications for VPS4B-deleted cancers.\",\n      \"evidence\": \"CRISPR and RNAi screens, genetic epistasis, ESCRT-III imaging, cell-cycle analysis, transcriptomics, and xenograft models across two studies\",\n      \"pmids\": [\"33326793\", \"31930723\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Degree of mechanistic non-redundancy between paralogs not fully dissected\", \"Basis of the immunomodulatory release upon co-depletion unresolved\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Established that VPS4B is individually essential in vivo despite paralog redundancy in culture, with knockout causing early embryonic lethality.\",\n      \"evidence\": \"Vps4b conditional knockout mice with timed embryo analysis and siRNA knockdown with qRT-PCR\",\n      \"pmids\": [\"33682352\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Cause of E9.5 lethality not mechanistically resolved\", \"Tissue-specific requirements not dissected\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Placed VPS4B in the autophagic degradation pathway controlling immune killing, showing its loss impairs autophagy and allows granzyme B accumulation that sensitizes tumor cells to CD8+ T cells.\",\n      \"evidence\": \"In vitro and in vivo CRISPR screens, autophagy flux assays, granzyme B accumulation, and orthotopic transplantation\",\n      \"pmids\": [\"35379808\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Step in autophagy requiring VPS4B not pinpointed\", \"Whether granzyme B clearance is direct autophagic substrate handling unclear\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Extended VPS4B's ESCRT-III recycling role to nuclear envelope repair, showing insufficient VPS4B impairs response to mechanical NE stress.\",\n      \"evidence\": \"VPS4B knockdown/expression comparison with nuclear deformation, DNA damage, and ESCRT-III dynamics imaging in glioblastoma cells\",\n      \"pmids\": [\"39540606\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Limited methodology described\", \"Quantitative contribution relative to VPS4A at the NE not established\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Implicated VPS4B in adipocyte lipid droplet release through an ANXA5 interaction modulated by O-GlcNAcylation, suggesting metabolic regulation of VPS4B activity.\",\n      \"evidence\": \"Co-culture, RNA-seq/proteomics, co-IP of VPS4B–ANXA5, siRNA knockdown, and in vivo tumor models\",\n      \"pmids\": [\"40410860\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Single-lab interaction with limited mechanistic resolution\", \"Site and functional impact of O-GlcNAc modification not mapped\", \"Reciprocal validation of VPS4B–ANXA5 binding not shown\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"It remains unknown how VPS4B's single ESCRT-III disassembly activity is differentially deployed and regulated across its distinct membrane contexts (endosomes, midbody, nuclear envelope) and how this connects mechanistically to downstream signaling outcomes such as Wnt and EGFR pathways.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structural model of the active VPS4B–ESCRT-III–cofactor assembly in human cells\", \"Determinants of context-specific recruitment unidentified\", \"Direct link between membrane-scission activity and transcriptional/signaling phenotypes unresolved\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140657\", \"supporting_discovery_ids\": [1, 7]},\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [1, 7]},\n      {\"term_id\": \"GO:0008092\", \"supporting_discovery_ids\": [0, 1]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005768\", \"supporting_discovery_ids\": [1, 2, 4]},\n      {\"term_id\": \"GO:0005635\", \"supporting_discovery_ids\": [11]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [1]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-5653656\", \"supporting_discovery_ids\": [1, 4, 3]},\n      {\"term_id\": \"R-HSA-1640170\", \"supporting_discovery_ids\": [7]},\n      {\"term_id\": \"R-HSA-9612973\", \"supporting_discovery_ids\": [10]}\n    ],\n    \"complexes\": [\"ESCRT-III\"],\n    \"partners\": [\"CHMP2A\", \"SBP1\", \"ALG-2\", \"ANXA5\", \"VPS4A\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":7,"faith_pct":85.71428571428571}}