{"gene":"VPS37B","run_date":"2026-06-11T09:02:06","timeline":{"discoveries":[{"year":2004,"finding":"VPS37B was identified as a subunit of the human ESCRT-I complex (~350 kDa), binding TSG101 at multiple sites including a putative coiled-coil region and a PTAP motif; VPS28 and TSG101 co-immunoprecipitated with VPS37B-FLAG, demonstrating a trimeric complex. VPS37B was also shown to relocalize to aberrant endosomal compartments when dominant-negative VPS4A (lacking ATPase activity) was expressed, and could recruit TSG101/ESCRT-I activity to rescue budding of Gag particles lacking native late domains.","method":"Co-immunoprecipitation, yeast two-hybrid, size-exclusion chromatography, dominant-negative VPS4A trapping assay, HIV-1 budding rescue assay","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP, functional rescue assay, and dominant-negative trapping across multiple orthogonal methods in a focused study","pmids":["15218037"],"is_preprint":false},{"year":2004,"finding":"VPS37B and VPS37C are partially redundant ESCRT-I components in mammalian cells; simultaneous depletion of both VPS37B and VPS37C more strongly inhibits ESCRT-I-dependent viral budding than depletion of either alone, establishing functional overlap between these paralogs within the ESCRT-I complex.","method":"siRNA knockdown combined with virus-like particle release assay","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — clean knockdown with defined viral budding readout, single lab, two methods","pmids":["15509564"],"is_preprint":false},{"year":2007,"finding":"Ebola virus matrix protein VP40 can redirect VPS37B from endosomes to the cell surface independently of TSG101 interaction, demonstrating that VPS37B is recruited to the plasma membrane during EBOV budding through a TSG101-independent mechanism.","method":"VP40 deletion analysis, virus-like particle release assay, confocal microscopy","journal":"The Journal of infectious diseases","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — confocal localization and functional budding assay, single lab, single paper","pmids":["17940959"],"is_preprint":false},{"year":2013,"finding":"VPS37B-containing ESCRT-I interacts more strongly with ALG-2 than TSG101 does; ALG-2 functions as a Ca2+-dependent adaptor bridging ALIX and ESCRT-I containing VPS37B or VPS37C to form a ternary ESCRT-I/ALIX/ALG-2 complex. This was demonstrated by Far-Western blot and pulldown assays with purified recombinant proteins.","method":"Far-Western blot with biotin-labeled ALG-2 probe, co-expression pulldown in HEK293T cells, in vitro binding assay with purified recombinant proteins","journal":"Bioscience, biotechnology, and biochemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vitro binding with purified proteins plus cell-based pulldown, single lab, two orthogonal methods","pmids":["23924735"],"is_preprint":false},{"year":2020,"finding":"Crystal structure of the human ESCRT-I headpiece comprising TSG101-VPS28-VPS37B-MVB12A was determined, revealing that ESCRT-I assembles into a helical filament with a 12-molecule repeat. Electron microscopy confirmed helical filament formation in solution. Mutation of VPS28 helical interface residues blocks filament formation in vitro and impairs autophagosome closure and HIV-1 release in human cells, demonstrating that ESCRT-I has an essential scaffolding role beyond being a simple adaptor.","method":"X-ray crystallography, negative-stain electron microscopy, site-directed mutagenesis, in vitro filament assay, autophagosome closure assay, HIV-1 release assay","journal":"Nature structural & molecular biology","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structure with mutagenesis validated by EM and two independent cellular functional assays in a single rigorous study","pmids":["32424346"],"is_preprint":false},{"year":2019,"finding":"SH3YL1 interacts with VPS37B through its C-terminal SH3 domain; this interaction is required for SH3YL1-mediated EGFR sorting into multivesicular bodies and for EGF trafficking from early to late endosomes. Loss of SH3YL1 prevents EGFR degradation, placing VPS37B downstream as the ESCRT-I docking point for SH3YL1 in the MVB sorting pathway.","method":"Co-immunoprecipitation, SH3 domain pulldown, SH3YL1 knockout cells with EGF trafficking and EGFR degradation readouts, confocal microscopy","journal":"Journal of cell science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP with domain mapping, KO cellular phenotype with defined trafficking readout, single lab","pmids":["31492760"],"is_preprint":false},{"year":2021,"finding":"VPS37B and VPS37C enable endocytosis of the mannose receptor in dendritic cells following antigen presentation, facilitating recognition of the HDM allergen Der p 1. CRISPR-mediated disruption of VPS37A/B in DCs reduced Th2 cytokine production and alleviated allergic rhinitis symptoms in a mouse model, placing VPS37B in the endocytic pathway responsible for allergen uptake.","method":"CRISPR/Cas9 knockout, RNA-seq, in vitro co-culture with T cells (cytokine measurement), in vivo mouse AR model with nasal DC administration","journal":"Biomaterials","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — CRISPR KO with both in vitro and in vivo functional readouts, single lab","pmids":["33895493"],"is_preprint":false},{"year":2021,"finding":"Concurrent knockdown of VPS37A and VPS37B destabilizes the ESCRT-I complex and triggers p21 (CDKN1A)-mediated inhibition of cell proliferation as well as a sterile NF-κB-driven inflammatory response in colorectal cancer cells. Additional co-silencing of VPS37C further potentiates these responses, demonstrating that VPS37 proteins are non-redundant stabilizers of ESCRT-I integrity whose loss causes defined stress signaling.","method":"siRNA knockdown (individual and combined), transcriptomic profiling, Western blot for ESCRT-I stability, proliferation assay, NF-κB reporter assay","journal":"Journal of cell science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — clean siRNA KD with multiple orthogonal readouts (proliferation, transcriptomics, complex stability), single lab","pmids":["33419951"],"is_preprint":false},{"year":2021,"finding":"CDIP1 preferentially associates with ESCRT-I complexes containing VPS37B or VPS37C (over VPS37A or VPS37D isoforms) in part through the adaptor function of ALG-2; co-expression of ALG-2 and VPS37B-containing ESCRT-I enhances CDIP1-induced caspase-3/7-mediated cell death, positioning VPS37B-ESCRT-I as a pro-apoptotic effector complex.","method":"Co-immunoprecipitation of GFP-CDIP1 with isoform-specific ESCRT-I complexes, caspase-3/7 activity assay, overexpression in HEK293 cells","journal":"International journal of molecular sciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP with isoform selectivity plus functional cell-death assay, single lab, two orthogonal methods","pmids":["33503978"],"is_preprint":false}],"current_model":"VPS37B is a core subunit of the human ESCRT-I heterotetrameric complex (with TSG101, VPS28, and MVB12), where it contributes to a helical scaffold that bridges ubiquitinated cargo sorting into multivesicular bodies, autophagosome closure, and enveloped virus budding; it interacts with TSG101 at multiple sites, serves as the docking point for SH3YL1 in EGFR/MVB sorting, binds ALG-2 to bridge ESCRT-I to ALIX and CDIP1, and is required for mannose-receptor-mediated allergen endocytosis in dendritic cells, with its loss destabilizing the ESCRT-I complex and triggering p21- and NF-κB-mediated stress responses."},"narrative":{"mechanistic_narrative":"VPS37B is a core subunit of the human ESCRT-I complex, where together with TSG101, VPS28, and an MVB12 subunit it forms a heterotetrameric headpiece that polymerizes into a helical filament with a 12-molecule repeat, conferring an essential scaffolding role required for autophagosome closure and HIV-1 release [PMID:15218037, PMID:32424346]. It engages TSG101 at multiple interfaces, including a putative coiled-coil region and a PTAP motif, and its incorporation into ESCRT-I supports ubiquitinated cargo sorting and enveloped virus budding [PMID:15218037]. VPS37B serves as the ESCRT-I docking point for SH3YL1, an interaction mediated by the SH3YL1 C-terminal SH3 domain that is needed for EGFR sorting into multivesicular bodies and its subsequent degradation [PMID:31492760]. Through the Ca2+-dependent adaptor ALG-2, VPS37B-containing ESCRT-I is bridged to ALIX and preferentially recruits the pro-apoptotic effector CDIP1, enhancing caspase-3/7-mediated cell death [PMID:23924735, PMID:33503978]. VPS37B is partially redundant with its paralog VPS37C in ESCRT-I-dependent budding, and concurrent loss of VPS37 proteins destabilizes ESCRT-I and triggers p21-mediated proliferation arrest and a sterile NF-κB inflammatory response [PMID:15509564, PMID:33419951]. Functionally, VPS37B also operates in the endocytic uptake of the mannose receptor in dendritic cells, contributing to allergen recognition and Th2 responses [PMID:33895493].","teleology":[{"year":2004,"claim":"Established VPS37B as a bona fide ESCRT-I subunit, answering whether it physically integrates into the TSG101/VPS28 machinery and participates in membrane budding.","evidence":"Reciprocal Co-IP, yeast two-hybrid, size-exclusion chromatography, dominant-negative VPS4A trapping, and HIV-1 Gag budding rescue in human cells","pmids":["15218037"],"confidence":"High","gaps":["Stoichiometry and architecture of the assembled complex not resolved at this stage","Cargo specificity of VPS37B-containing ESCRT-I not defined"]},{"year":2004,"claim":"Showed that VPS37B and its paralog VPS37C are functionally overlapping within ESCRT-I, explaining why single depletion gives partial phenotypes.","evidence":"siRNA knockdown of VPS37B and VPS37C with virus-like particle release readout","pmids":["15509564"],"confidence":"Medium","gaps":["Degree of redundancy with VPS37A/VPS37D not addressed","Distinct vs shared cargo for each paralog not mapped"]},{"year":2007,"claim":"Revealed a TSG101-independent route for VPS37B recruitment to the plasma membrane, showing that viral matrix proteins can co-opt VPS37B directly.","evidence":"Ebola VP40 deletion analysis, VLP release assay, and confocal microscopy","pmids":["17940959"],"confidence":"Medium","gaps":["Molecular interface for the TSG101-independent recruitment not identified","Single virus context, generality unknown"]},{"year":2013,"claim":"Identified ALG-2 as a Ca2+-dependent adaptor that preferentially bridges VPS37B-containing ESCRT-I to ALIX, defining how this isoform-specific complex is linked to ALIX-dependent functions.","evidence":"Far-Western blot, co-expression pulldown, and in vitro binding with purified recombinant proteins","pmids":["23924735"],"confidence":"Medium","gaps":["Cellular consequence of the ESCRT-I/ALIX/ALG-2 ternary complex not yet established here","Binding site on VPS37B-ESCRT-I not mapped"]},{"year":2019,"claim":"Placed VPS37B as the ESCRT-I docking point for SH3YL1 in receptor downregulation, linking the subunit to EGFR sorting and degradation.","evidence":"Co-IP, SH3 domain pulldown, and SH3YL1 knockout cells with EGF trafficking and EGFR degradation readouts","pmids":["31492760"],"confidence":"Medium","gaps":["Whether SH3YL1 binding requires intact ESCRT-I assembly not tested","Structural basis of the SH3-VPS37B interaction unknown"]},{"year":2020,"claim":"Defined the structural basis of ESCRT-I function, showing the TSG101-VPS28-VPS37B-MVB12A headpiece polymerizes into a helical filament essential for autophagosome closure and viral release.","evidence":"X-ray crystallography, negative-stain EM, interface mutagenesis, in vitro filament assay, and cellular autophagosome closure and HIV-1 release assays","pmids":["32424346"],"confidence":"High","gaps":["Specific contribution of VPS37B (vs other VPS37 paralogs) to filament geometry not isolated","Regulation of filament assembly in vivo not defined"]},{"year":2021,"claim":"Demonstrated that VPS37 proteins are non-redundant stabilizers of ESCRT-I whose combined loss produces defined stress signaling, linking complex integrity to proliferation control and inflammation.","evidence":"Individual and combined siRNA knockdown, transcriptomics, Western blot for ESCRT-I stability, proliferation and NF-κB reporter assays in colorectal cancer cells","pmids":["33419951"],"confidence":"Medium","gaps":["Direct trigger linking ESCRT-I destabilization to p21 and NF-κB not mechanistically resolved","VPS37B-specific contribution vs VPS37A/C not separated"]},{"year":2021,"claim":"Connected VPS37B-containing ESCRT-I to programmed cell death by showing ALG-2-dependent recruitment of CDIP1 enhances caspase activation.","evidence":"Co-IP of GFP-CDIP1 with isoform-specific ESCRT-I complexes and caspase-3/7 activity assays in HEK293 cells","pmids":["33503978"],"confidence":"Medium","gaps":["Physiological setting where this pro-apoptotic complex acts not established","Whether CDIP1 binding requires filament assembly unknown"]},{"year":2021,"claim":"Extended VPS37B function to immune endocytosis, showing it enables mannose-receptor-mediated allergen uptake in dendritic cells and shapes Th2 responses.","evidence":"CRISPR/Cas9 knockout, RNA-seq, T-cell co-culture cytokine assays, and an in vivo mouse allergic rhinitis model","pmids":["33895493"],"confidence":"Medium","gaps":["Direct interaction of VPS37B with the mannose receptor pathway not demonstrated","VPS37B-specific vs VPS37A contribution not fully separated"]},{"year":null,"claim":"How VPS37B isoform identity selects distinct cargo and effector outcomes (EGFR sorting, ALIX/CDIP1 apoptosis, allergen endocytosis) versus the redundant budding role remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structural map of VPS37B-specific binding surfaces for SH3YL1, ALG-2, or CDIP1","Mechanism coupling ESCRT-I destabilization to p21/NF-κB signaling unknown","In vivo physiological requirement for VPS37B in mammalian tissues not defined"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[0,5,3]},{"term_id":"GO:0005198","term_label":"structural molecule activity","supporting_discovery_ids":[4]}],"localization":[{"term_id":"GO:0005768","term_label":"endosome","supporting_discovery_ids":[0,5]},{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[2]}],"pathway":[{"term_id":"R-HSA-5653656","term_label":"Vesicle-mediated transport","supporting_discovery_ids":[0,5]},{"term_id":"R-HSA-9612973","term_label":"Autophagy","supporting_discovery_ids":[4]},{"term_id":"R-HSA-5357801","term_label":"Programmed Cell Death","supporting_discovery_ids":[8]}],"complexes":["ESCRT-I"],"partners":["TSG101","VPS28","MVB12A","ALG-2","ALIX","SH3YL1","CDIP1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q9H9H4","full_name":"Vacuolar protein sorting-associated protein 37B","aliases":["ESCRT-I complex subunit VPS37B"],"length_aa":285,"mass_kda":31.3,"function":"Component of the ESCRT-I complex, a regulator of vesicular trafficking process. Required for the sorting of endocytic ubiquitinated cargos into multivesicular bodies. May be involved in cell growth and differentiation","subcellular_location":"Late endosome membrane","url":"https://www.uniprot.org/uniprotkb/Q9H9H4/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/VPS37B","classification":"Not Classified","n_dependent_lines":4,"n_total_lines":1208,"dependency_fraction":0.0033112582781456954},"opencell":{"profiled":true,"resolved_as":"","ensg_id":"ENSG00000139722","cell_line_id":"CID000791","localizations":[{"compartment":"cytoplasmic","grade":3},{"compartment":"vesicles","grade":2}],"interactors":[{"gene":"MVB12A","stoichiometry":10.0},{"gene":"TSG101","stoichiometry":10.0},{"gene":"VPS28","stoichiometry":10.0},{"gene":"MVB12B","stoichiometry":10.0},{"gene":"UMAD1","stoichiometry":4.0},{"gene":"GOLGA2","stoichiometry":0.2},{"gene":"VPS25","stoichiometry":0.2},{"gene":"CEP55","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/target/CID000791","total_profiled":1310},"omim":[{"mim_id":"610038","title":"VPS37C SUBUNIT OF ESCRT-I; VPS37C","url":"https://www.omim.org/entry/610038"},{"mim_id":"610037","title":"VPS37B SUBUNIT OF ESCRT-I; VPS37B","url":"https://www.omim.org/entry/610037"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Uncertain","locations":[{"location":"Cytosol","reliability":"Uncertain"},{"location":"Primary cilium","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/VPS37B"},"hgnc":{"alias_symbol":["FLJ12750"],"prev_symbol":[]},"alphafold":{"accession":"Q9H9H4","domains":[{"cath_id":"1.20.5","chopping":"14-83","consensus_level":"medium","plddt":93.9389,"start":14,"end":83},{"cath_id":"1.10.287","chopping":"102-164","consensus_level":"medium","plddt":95.5694,"start":102,"end":164}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9H9H4","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9H9H4-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9H9H4-F1-predicted_aligned_error_v6.png","plddt_mean":75.31},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=VPS37B","jax_strain_url":"https://www.jax.org/strain/search?query=VPS37B"},"sequence":{"accession":"Q9H9H4","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9H9H4.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9H9H4/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9H9H4"}},"corpus_meta":[{"pmid":"15218037","id":"PMC_15218037","title":"The human endosomal sorting complex required for transport (ESCRT-I) and its role in HIV-1 budding.","date":"2004","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/15218037","citation_count":139,"is_preprint":false},{"pmid":"29180230","id":"PMC_29180230","title":"Glucocorticoids, genes and brain function.","date":"2017","source":"Progress in neuro-psychopharmacology & biological psychiatry","url":"https://pubmed.ncbi.nlm.nih.gov/29180230","citation_count":107,"is_preprint":false},{"pmid":"31377428","id":"PMC_31377428","title":"Identification of molecular signatures and pathways to identify novel therapeutic targets in Alzheimer's disease: Insights from a systems biomedicine perspective.","date":"2019","source":"Genomics","url":"https://pubmed.ncbi.nlm.nih.gov/31377428","citation_count":91,"is_preprint":false},{"pmid":"15509564","id":"PMC_15509564","title":"Identification of human VPS37C, a component of endosomal sorting complex required for transport-I important for viral budding.","date":"2004","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/15509564","citation_count":77,"is_preprint":false},{"pmid":"27922854","id":"PMC_27922854","title":"Identification of HIV infection-related DNA methylation sites and advanced epigenetic aging in HIV-positive, treatment-naive U.S. veterans.","date":"2017","source":"AIDS (London, England)","url":"https://pubmed.ncbi.nlm.nih.gov/27922854","citation_count":50,"is_preprint":false},{"pmid":"32424346","id":"PMC_32424346","title":"A helical assembly of human ESCRT-I scaffolds reverse-topology membrane scission.","date":"2020","source":"Nature structural & molecular biology","url":"https://pubmed.ncbi.nlm.nih.gov/32424346","citation_count":48,"is_preprint":false},{"pmid":"21733561","id":"PMC_21733561","title":"Frameshift mutations of vacuolar protein sorting genes in gastric and colorectal cancers with microsatellite instability.","date":"2011","source":"Human pathology","url":"https://pubmed.ncbi.nlm.nih.gov/21733561","citation_count":41,"is_preprint":false},{"pmid":"17940959","id":"PMC_17940959","title":"Involvement of vacuolar protein sorting pathway in Ebola virus release independent of TSG101 interaction.","date":"2007","source":"The Journal of infectious diseases","url":"https://pubmed.ncbi.nlm.nih.gov/17940959","citation_count":38,"is_preprint":false},{"pmid":"23924735","id":"PMC_23924735","title":"VPS37 isoforms differentially modulate the ternary complex formation of ALIX, ALG-2, and ESCRT-I.","date":"2013","source":"Bioscience, biotechnology, and biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/23924735","citation_count":26,"is_preprint":false},{"pmid":"33419951","id":"PMC_33419951","title":"Concurrent depletion of Vps37 proteins evokes ESCRT-I destabilization and profound cellular stress responses.","date":"2021","source":"Journal of cell 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VPS37B was also shown to relocalize to aberrant endosomal compartments when dominant-negative VPS4A (lacking ATPase activity) was expressed, and could recruit TSG101/ESCRT-I activity to rescue budding of Gag particles lacking native late domains.\",\n      \"method\": \"Co-immunoprecipitation, yeast two-hybrid, size-exclusion chromatography, dominant-negative VPS4A trapping assay, HIV-1 budding rescue assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP, functional rescue assay, and dominant-negative trapping across multiple orthogonal methods in a focused study\",\n      \"pmids\": [\"15218037\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"VPS37B and VPS37C are partially redundant ESCRT-I components in mammalian cells; simultaneous depletion of both VPS37B and VPS37C more strongly inhibits ESCRT-I-dependent viral budding than depletion of either alone, establishing functional overlap between these paralogs within the ESCRT-I complex.\",\n      \"method\": \"siRNA knockdown combined with virus-like particle release assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean knockdown with defined viral budding readout, single lab, two methods\",\n      \"pmids\": [\"15509564\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"Ebola virus matrix protein VP40 can redirect VPS37B from endosomes to the cell surface independently of TSG101 interaction, demonstrating that VPS37B is recruited to the plasma membrane during EBOV budding through a TSG101-independent mechanism.\",\n      \"method\": \"VP40 deletion analysis, virus-like particle release assay, confocal microscopy\",\n      \"journal\": \"The Journal of infectious diseases\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — confocal localization and functional budding assay, single lab, single paper\",\n      \"pmids\": [\"17940959\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"VPS37B-containing ESCRT-I interacts more strongly with ALG-2 than TSG101 does; ALG-2 functions as a Ca2+-dependent adaptor bridging ALIX and ESCRT-I containing VPS37B or VPS37C to form a ternary ESCRT-I/ALIX/ALG-2 complex. This was demonstrated by Far-Western blot and pulldown assays with purified recombinant proteins.\",\n      \"method\": \"Far-Western blot with biotin-labeled ALG-2 probe, co-expression pulldown in HEK293T cells, in vitro binding assay with purified recombinant proteins\",\n      \"journal\": \"Bioscience, biotechnology, and biochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vitro binding with purified proteins plus cell-based pulldown, single lab, two orthogonal methods\",\n      \"pmids\": [\"23924735\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Crystal structure of the human ESCRT-I headpiece comprising TSG101-VPS28-VPS37B-MVB12A was determined, revealing that ESCRT-I assembles into a helical filament with a 12-molecule repeat. Electron microscopy confirmed helical filament formation in solution. Mutation of VPS28 helical interface residues blocks filament formation in vitro and impairs autophagosome closure and HIV-1 release in human cells, demonstrating that ESCRT-I has an essential scaffolding role beyond being a simple adaptor.\",\n      \"method\": \"X-ray crystallography, negative-stain electron microscopy, site-directed mutagenesis, in vitro filament assay, autophagosome closure assay, HIV-1 release assay\",\n      \"journal\": \"Nature structural & molecular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structure with mutagenesis validated by EM and two independent cellular functional assays in a single rigorous study\",\n      \"pmids\": [\"32424346\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"SH3YL1 interacts with VPS37B through its C-terminal SH3 domain; this interaction is required for SH3YL1-mediated EGFR sorting into multivesicular bodies and for EGF trafficking from early to late endosomes. Loss of SH3YL1 prevents EGFR degradation, placing VPS37B downstream as the ESCRT-I docking point for SH3YL1 in the MVB sorting pathway.\",\n      \"method\": \"Co-immunoprecipitation, SH3 domain pulldown, SH3YL1 knockout cells with EGF trafficking and EGFR degradation readouts, confocal microscopy\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP with domain mapping, KO cellular phenotype with defined trafficking readout, single lab\",\n      \"pmids\": [\"31492760\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"VPS37B and VPS37C enable endocytosis of the mannose receptor in dendritic cells following antigen presentation, facilitating recognition of the HDM allergen Der p 1. CRISPR-mediated disruption of VPS37A/B in DCs reduced Th2 cytokine production and alleviated allergic rhinitis symptoms in a mouse model, placing VPS37B in the endocytic pathway responsible for allergen uptake.\",\n      \"method\": \"CRISPR/Cas9 knockout, RNA-seq, in vitro co-culture with T cells (cytokine measurement), in vivo mouse AR model with nasal DC administration\",\n      \"journal\": \"Biomaterials\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — CRISPR KO with both in vitro and in vivo functional readouts, single lab\",\n      \"pmids\": [\"33895493\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Concurrent knockdown of VPS37A and VPS37B destabilizes the ESCRT-I complex and triggers p21 (CDKN1A)-mediated inhibition of cell proliferation as well as a sterile NF-κB-driven inflammatory response in colorectal cancer cells. Additional co-silencing of VPS37C further potentiates these responses, demonstrating that VPS37 proteins are non-redundant stabilizers of ESCRT-I integrity whose loss causes defined stress signaling.\",\n      \"method\": \"siRNA knockdown (individual and combined), transcriptomic profiling, Western blot for ESCRT-I stability, proliferation assay, NF-κB reporter assay\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean siRNA KD with multiple orthogonal readouts (proliferation, transcriptomics, complex stability), single lab\",\n      \"pmids\": [\"33419951\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"CDIP1 preferentially associates with ESCRT-I complexes containing VPS37B or VPS37C (over VPS37A or VPS37D isoforms) in part through the adaptor function of ALG-2; co-expression of ALG-2 and VPS37B-containing ESCRT-I enhances CDIP1-induced caspase-3/7-mediated cell death, positioning VPS37B-ESCRT-I as a pro-apoptotic effector complex.\",\n      \"method\": \"Co-immunoprecipitation of GFP-CDIP1 with isoform-specific ESCRT-I complexes, caspase-3/7 activity assay, overexpression in HEK293 cells\",\n      \"journal\": \"International journal of molecular sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP with isoform selectivity plus functional cell-death assay, single lab, two orthogonal methods\",\n      \"pmids\": [\"33503978\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"VPS37B is a core subunit of the human ESCRT-I heterotetrameric complex (with TSG101, VPS28, and MVB12), where it contributes to a helical scaffold that bridges ubiquitinated cargo sorting into multivesicular bodies, autophagosome closure, and enveloped virus budding; it interacts with TSG101 at multiple sites, serves as the docking point for SH3YL1 in EGFR/MVB sorting, binds ALG-2 to bridge ESCRT-I to ALIX and CDIP1, and is required for mannose-receptor-mediated allergen endocytosis in dendritic cells, with its loss destabilizing the ESCRT-I complex and triggering p21- and NF-κB-mediated stress responses.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"VPS37B is a core subunit of the human ESCRT-I complex, where together with TSG101, VPS28, and an MVB12 subunit it forms a heterotetrameric headpiece that polymerizes into a helical filament with a 12-molecule repeat, conferring an essential scaffolding role required for autophagosome closure and HIV-1 release [#0, #4]. It engages TSG101 at multiple interfaces, including a putative coiled-coil region and a PTAP motif, and its incorporation into ESCRT-I supports ubiquitinated cargo sorting and enveloped virus budding [#0]. VPS37B serves as the ESCRT-I docking point for SH3YL1, an interaction mediated by the SH3YL1 C-terminal SH3 domain that is needed for EGFR sorting into multivesicular bodies and its subsequent degradation [#5]. Through the Ca2+-dependent adaptor ALG-2, VPS37B-containing ESCRT-I is bridged to ALIX and preferentially recruits the pro-apoptotic effector CDIP1, enhancing caspase-3/7-mediated cell death [#3, #8]. VPS37B is partially redundant with its paralog VPS37C in ESCRT-I-dependent budding, and concurrent loss of VPS37 proteins destabilizes ESCRT-I and triggers p21-mediated proliferation arrest and a sterile NF-\\u03baB inflammatory response [#1, #7]. Functionally, VPS37B also operates in the endocytic uptake of the mannose receptor in dendritic cells, contributing to allergen recognition and Th2 responses [#6].\",\n  \"teleology\": [\n    {\n      \"year\": 2004,\n      \"claim\": \"Established VPS37B as a bona fide ESCRT-I subunit, answering whether it physically integrates into the TSG101/VPS28 machinery and participates in membrane budding.\",\n      \"evidence\": \"Reciprocal Co-IP, yeast two-hybrid, size-exclusion chromatography, dominant-negative VPS4A trapping, and HIV-1 Gag budding rescue in human cells\",\n      \"pmids\": [\"15218037\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Stoichiometry and architecture of the assembled complex not resolved at this stage\", \"Cargo specificity of VPS37B-containing ESCRT-I not defined\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Showed that VPS37B and its paralog VPS37C are functionally overlapping within ESCRT-I, explaining why single depletion gives partial phenotypes.\",\n      \"evidence\": \"siRNA knockdown of VPS37B and VPS37C with virus-like particle release readout\",\n      \"pmids\": [\"15509564\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Degree of redundancy with VPS37A/VPS37D not addressed\", \"Distinct vs shared cargo for each paralog not mapped\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Revealed a TSG101-independent route for VPS37B recruitment to the plasma membrane, showing that viral matrix proteins can co-opt VPS37B directly.\",\n      \"evidence\": \"Ebola VP40 deletion analysis, VLP release assay, and confocal microscopy\",\n      \"pmids\": [\"17940959\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular interface for the TSG101-independent recruitment not identified\", \"Single virus context, generality unknown\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Identified ALG-2 as a Ca2+-dependent adaptor that preferentially bridges VPS37B-containing ESCRT-I to ALIX, defining how this isoform-specific complex is linked to ALIX-dependent functions.\",\n      \"evidence\": \"Far-Western blot, co-expression pulldown, and in vitro binding with purified recombinant proteins\",\n      \"pmids\": [\"23924735\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Cellular consequence of the ESCRT-I/ALIX/ALG-2 ternary complex not yet established here\", \"Binding site on VPS37B-ESCRT-I not mapped\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Placed VPS37B as the ESCRT-I docking point for SH3YL1 in receptor downregulation, linking the subunit to EGFR sorting and degradation.\",\n      \"evidence\": \"Co-IP, SH3 domain pulldown, and SH3YL1 knockout cells with EGF trafficking and EGFR degradation readouts\",\n      \"pmids\": [\"31492760\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether SH3YL1 binding requires intact ESCRT-I assembly not tested\", \"Structural basis of the SH3-VPS37B interaction unknown\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Defined the structural basis of ESCRT-I function, showing the TSG101-VPS28-VPS37B-MVB12A headpiece polymerizes into a helical filament essential for autophagosome closure and viral release.\",\n      \"evidence\": \"X-ray crystallography, negative-stain EM, interface mutagenesis, in vitro filament assay, and cellular autophagosome closure and HIV-1 release assays\",\n      \"pmids\": [\"32424346\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Specific contribution of VPS37B (vs other VPS37 paralogs) to filament geometry not isolated\", \"Regulation of filament assembly in vivo not defined\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Demonstrated that VPS37 proteins are non-redundant stabilizers of ESCRT-I whose combined loss produces defined stress signaling, linking complex integrity to proliferation control and inflammation.\",\n      \"evidence\": \"Individual and combined siRNA knockdown, transcriptomics, Western blot for ESCRT-I stability, proliferation and NF-\\u03baB reporter assays in colorectal cancer cells\",\n      \"pmids\": [\"33419951\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct trigger linking ESCRT-I destabilization to p21 and NF-\\u03baB not mechanistically resolved\", \"VPS37B-specific contribution vs VPS37A/C not separated\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Connected VPS37B-containing ESCRT-I to programmed cell death by showing ALG-2-dependent recruitment of CDIP1 enhances caspase activation.\",\n      \"evidence\": \"Co-IP of GFP-CDIP1 with isoform-specific ESCRT-I complexes and caspase-3/7 activity assays in HEK293 cells\",\n      \"pmids\": [\"33503978\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Physiological setting where this pro-apoptotic complex acts not established\", \"Whether CDIP1 binding requires filament assembly unknown\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Extended VPS37B function to immune endocytosis, showing it enables mannose-receptor-mediated allergen uptake in dendritic cells and shapes Th2 responses.\",\n      \"evidence\": \"CRISPR/Cas9 knockout, RNA-seq, T-cell co-culture cytokine assays, and an in vivo mouse allergic rhinitis model\",\n      \"pmids\": [\"33895493\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct interaction of VPS37B with the mannose receptor pathway not demonstrated\", \"VPS37B-specific vs VPS37A contribution not fully separated\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How VPS37B isoform identity selects distinct cargo and effector outcomes (EGFR sorting, ALIX/CDIP1 apoptosis, allergen endocytosis) versus the redundant budding role remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structural map of VPS37B-specific binding surfaces for SH3YL1, ALG-2, or CDIP1\", \"Mechanism coupling ESCRT-I destabilization to p21/NF-\\u03baB signaling unknown\", \"In vivo physiological requirement for VPS37B in mammalian tissues not defined\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [0, 5, 3]},\n      {\"term_id\": \"GO:0005198\", \"supporting_discovery_ids\": [4]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005768\", \"supporting_discovery_ids\": [0, 5]},\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [2]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-5653656\", \"supporting_discovery_ids\": [0, 5]},\n      {\"term_id\": \"R-HSA-9612973\", \"supporting_discovery_ids\": [4]},\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [8]}\n    ],\n    \"complexes\": [\"ESCRT-I\"],\n    \"partners\": [\"TSG101\", \"VPS28\", \"MVB12A\", \"ALG-2\", \"ALIX\", \"SH3YL1\", \"CDIP1\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}