{"gene":"VPS37C","run_date":"2026-06-11T09:02:06","timeline":{"discoveries":[{"year":2004,"finding":"VPS37C is a component of mammalian ESCRT-I: it binds to a domain toward the C-terminus of TSG101 and forms a ternary complex with TSG101 and VPS28. VPS37C also binds the class E VPS factor HRS. VPS37C is recruited to aberrant endosomes induced by overexpression of TSG101, HRS, or dominant-negative VPS4. Depletion of VPS37C inhibits PTAP-mediated (ESCRT-I-dependent) retroviral budding but not PPPY-mediated (ESCRT-I-independent) budding. Direct fusion of VPS37C to HIV-1 Gag rescues budding of a PTAP-deleted Gag.","method":"Yeast two-hybrid screen, co-immunoprecipitation, subcellular localization by overexpression/dominant-negative, siRNA depletion with viral budding assay, Gag-VPS37C fusion rescue experiment","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (Y2H, Co-IP, localization, depletion phenotype, fusion rescue) in a single focused study establishing ESCRT-I membership and function","pmids":["15509564"],"is_preprint":false},{"year":2008,"finding":"VPS37C (ESCRT-I) is required for HIV-1 Gag PTAP-dependent budding but not for ASV Gag PPPY-dependent budding: endogenous VPS37C depletion blocks HIV-1 release while having little effect on ASV release, demonstrating that ASV and HIV-1 utilize different ESCRT-I requirements.","method":"siRNA depletion of endogenous VPS37C combined with viral particle release assays; Gag-ESCRT fusion rescue experiments","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal depletion and rescue experiments across two viral systems, consistent with and extending prior work","pmids":["18723511"],"is_preprint":false},{"year":2011,"finding":"VPS37C-containing ESCRT-I is distinct from a UBAP1/VPS37A-containing endosome-specific ESCRT-I complex: UBAP1 associates with a fraction of TSG101 that also contains VPS37A but not VPS37C, indicating that VPS37C defines a separate ESCRT-I complex isoform.","method":"Co-immunoprecipitation, siRNA knockdown, endosomal sorting assays (EGFR degradation)","journal":"Current biology : CB","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP demonstrating exclusion of VPS37C from the UBAP1/VPS37A complex, replicated with functional assays","pmids":["21757351"],"is_preprint":false},{"year":2011,"finding":"TBK1 directly interacts with VPS37C and phosphorylates it, attenuating PTAP-dependent retroviral budding. TBK1 overexpression reduces HIV-1 pseudovirus release; TBK1 depletion or kinase-inactive TBK1 (K38A) enhances PTAP-dependent budding. This effect is independent of type I interferon signaling.","method":"Co-immunoprecipitation (TBK1–VPS37C interaction), shRNA knockdown, TBK1 kinase-dead mutant overexpression, viral budding assays in TBK1-knockout MEFs","journal":"Journal of immunology (Baltimore, Md. : 1950)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP interaction plus kinase-dead mutant phenotype and KO MEF experiments from a single lab; phosphorylation of VPS37C inferred but in vitro kinase assay not explicitly described in abstract","pmids":["21270402"],"is_preprint":false},{"year":2013,"finding":"VPS37C-containing ESCRT-I interacts with ALG-2 more strongly than TSG101 does. ALG-2 acts as a Ca2+-dependent adaptor bridging ALIX and ESCRT-I (including VPS37B- and VPS37C-containing complexes) to form a ternary ESCRT-I/ALIX/ALG-2 complex.","method":"Far-Western blot with biotin-labeled ALG-2 probe, pulldown assay of recombinant ESCRT-I complexes expressed 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 reconstitution with purified proteins plus cell-based pulldown; single lab with two orthogonal methods","pmids":["23924735"],"is_preprint":false},{"year":2021,"finding":"CDIP1 preferentially associates with ESCRT-I containing VPS37B or VPS37C (over other VPS37 isoforms), in part through the adaptor function of ALG-2. Co-expression of ALG-2 and VPS37C-containing ESCRT-I enhances CDIP1-induced caspase-3/7-mediated cell death.","method":"Co-immunoprecipitation of GFP-CDIP1 with ESCRT-I isoforms, caspase-3/7 cell death assay with overexpression in HEK293 cells","journal":"International journal of molecular sciences","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — single Co-IP with isoform specificity plus functional cell death assay; single lab","pmids":["33503978"],"is_preprint":false},{"year":2021,"finding":"Concurrent knockdown of VPS37A, VPS37B, and VPS37C destabilizes ESCRT-I and triggers p21/CDKN1A-mediated inhibition of cell proliferation and NF-κB-driven sterile inflammatory response. VPS37C co-silencing potentiates these responses induced by VPS37A/B double knockdown, indicating non-redundant roles of VPS37C within ESCRT-I.","method":"siRNA knockdown (individual and combined), transcriptomic profiling, Western blot for ESCRT-I stability, NF-κB reporter and p21 assessment","journal":"Journal of cell science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic epistasis by combinatorial knockdown with defined transcriptional phenotype; single lab with multiple readouts","pmids":["33419951"],"is_preprint":false},{"year":2023,"finding":"VPS37C interacts with EKLF/KLF1 transcription factor and prevents K48-linked polyubiquitination of EKLF, thereby blocking proteasome-mediated EKLF degradation. VPS37C overexpression promotes erythroid differentiation of MEL cells (increased EKLF target gene expression and benzidine-positive cells); VPS37C knockdown inhibits differentiation, and EKLF re-expression in VPS37C-knockdown cells restores erythroid gene expression and hemoglobin production.","method":"Co-immunoprecipitation (VPS37C–EKLF interaction), ubiquitination assay (K48-linkage specific), overexpression and siRNA knockdown in MEL cells with HMBA-induced differentiation, rescue experiment by EKLF re-expression","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP plus ubiquitination assay plus loss-of-function/rescue in a single lab with multiple orthogonal methods","pmids":["37307706"],"is_preprint":false},{"year":2024,"finding":"VPS37C was identified as a novel intracellular binding target of hydroxychloroquine using the POST-IT non-diffusive proximity tagging system in live cells.","method":"POST-IT proximity tagging (engineered PafA-HaloTag fusion transferring Pup to proximal proteins upon small-molecule binding) in live cells","journal":"eLife","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single novel method from a single lab; mechanistic consequences of VPS37C–hydroxychloroquine interaction not characterized in the abstract","pmids":["39728918"],"is_preprint":false}],"current_model":"VPS37C is a core subunit of mammalian ESCRT-I that assembles with TSG101 and VPS28 into a distinct complex isoform (separate from the UBAP1/VPS37A-containing endosome-specific ESCRT-I); it participates in PTAP-dependent retroviral budding, is phosphorylated by TBK1 to attenuate this budding, bridges ESCRT-I to ALIX via Ca2+-dependent ALG-2 adaptor function, stabilizes the EKLF transcription factor against K48-linked ubiquitin–proteasome degradation to promote erythroid differentiation, and contributes to overall ESCRT-I structural integrity such that its depletion—especially combined with VPS37A/B depletion—triggers NF-κB-driven inflammatory stress responses and cell-cycle arrest."},"narrative":{"mechanistic_narrative":"VPS37C is a core subunit of mammalian ESCRT-I that assembles with TSG101 and VPS28 into a ternary complex and also binds the class E VPS factor HRS, defining a complex isoform distinct from the endosome-specific UBAP1/VPS37A-containing ESCRT-I [PMID:15509564, PMID:21757351]. In this capacity it is required for PTAP-dependent (ESCRT-I-dependent) retroviral budding but dispensable for PPPY-dependent budding, as shown by depletion phenotypes and rescue when VPS37C is fused directly to a PTAP-deleted HIV-1 Gag [PMID:15509564, PMID:18723511]. This budding function is negatively regulated by TBK1, which directly binds and phosphorylates VPS37C to attenuate PTAP-dependent release independently of type I interferon signaling [PMID:21270402]. VPS37C-containing ESCRT-I is bridged to the accessory factor ALIX through the Ca2+-dependent adaptor ALG-2, forming an ESCRT-I/ALIX/ALG-2 ternary complex, and this same ALG-2 adaptor links VPS37C-containing ESCRT-I to CDIP1 to promote caspase-3/7-mediated cell death [PMID:23924735, PMID:33503978]. VPS37C contributes non-redundantly to overall ESCRT-I structural integrity: combined depletion of VPS37A/B/C destabilizes the complex and triggers p21/CDKN1A-mediated proliferation arrest and NF-κB-driven sterile inflammatory responses [PMID:33419951]. Beyond its ESCRT role, VPS37C stabilizes the EKLF/KLF1 transcription factor by blocking its K48-linked polyubiquitination and proteasomal degradation, thereby promoting erythroid differentiation [PMID:37307706].","teleology":[{"year":2004,"claim":"Established VPS37C as a bona fide ESCRT-I subunit and connected it functionally to ESCRT-dependent membrane budding, answering whether it is a structural component versus a peripheral factor.","evidence":"Yeast two-hybrid, Co-IP forming a TSG101/VPS28 ternary complex, localization to aberrant endosomes, siRNA depletion blocking PTAP-dependent budding, and Gag-VPS37C fusion rescue","pmids":["15509564"],"confidence":"High","gaps":["Stoichiometry and structural organization within ESCRT-I not resolved","Endogenous cargo sorting role distinct from viral budding not defined"]},{"year":2008,"claim":"Clarified that PTAP- versus PPPY-dependent viral budding pathways have divergent ESCRT-I requirements, with VPS37C specifically needed for HIV-1 but not ASV release.","evidence":"siRNA depletion of endogenous VPS37C with viral particle release assays across two retroviral systems plus fusion rescue","pmids":["18723511"],"confidence":"High","gaps":["Molecular basis for late-domain selectivity not detailed","Role of other VPS37 isoforms in the same assays not contrasted"]},{"year":2011,"claim":"Demonstrated that VPS37C defines a distinct ESCRT-I isoform separate from the UBAP1/VPS37A endosomal complex, addressing whether VPS37 paralogs are interchangeable.","evidence":"Reciprocal Co-IP showing UBAP1 associates with VPS37A but not VPS37C, with EGFR-degradation endosomal sorting assays","pmids":["21757351"],"confidence":"High","gaps":["Cellular contexts that select one isoform over another unknown","Functional consequences of isoform identity for distinct cargoes not mapped"]},{"year":2011,"claim":"Identified TBK1 as a direct regulator of VPS37C, establishing a kinase-mediated brake on ESCRT-dependent budding outside of interferon signaling.","evidence":"Co-IP of TBK1–VPS37C, shRNA knockdown, kinase-dead K38A mutant, and budding assays in TBK1-knockout MEFs","pmids":["21270402"],"confidence":"Medium","gaps":["In vitro kinase assay confirming direct phosphorylation not described","Phosphorylation site(s) on VPS37C not mapped"]},{"year":2013,"claim":"Defined how VPS37C-containing ESCRT-I couples to the ALIX branch, showing ALG-2 acts as a Ca2+-dependent bridge into an ESCRT-I/ALIX/ALG-2 ternary complex.","evidence":"Far-Western with ALG-2 probe, pulldown of recombinant ESCRT-I complexes, and in vitro binding with purified proteins","pmids":["23924735"],"confidence":"Medium","gaps":["Physiological process requiring this Ca2+-dependent bridge not established","Single-lab in vitro reconstitution"]},{"year":2021,"claim":"Linked VPS37C-containing ESCRT-I to programmed cell death by showing isoform-selective association with CDIP1 via ALG-2 that potentiates caspase activation.","evidence":"Co-IP of GFP-CDIP1 with ESCRT-I isoforms and caspase-3/7 cell death assays in HEK293 cells","pmids":["33503978"],"confidence":"Medium","gaps":["Endogenous (non-overexpression) relevance not shown","Mechanism connecting ESCRT-I/CDIP1 to caspase activation unresolved"]},{"year":2021,"claim":"Showed VPS37C contributes non-redundantly to ESCRT-I integrity, with combinatorial loss triggering cell-cycle arrest and sterile inflammation.","evidence":"Individual and combined siRNA knockdown, transcriptomics, ESCRT-I stability blots, NF-κB reporter and p21 readouts","pmids":["33419951"],"confidence":"Medium","gaps":["Direct trigger linking ESCRT-I destabilization to NF-κB not identified","Single-knockdown VPS37C phenotype relatively mild"]},{"year":2023,"claim":"Revealed a non-ESCRT function in which VPS37C stabilizes the EKLF transcription factor to drive erythroid differentiation, expanding its role beyond membrane trafficking.","evidence":"Co-IP, K48-linkage-specific ubiquitination assay, overexpression/knockdown in MEL cells with induced differentiation, and EKLF re-expression rescue","pmids":["37307706"],"confidence":"Medium","gaps":["Whether stabilization requires ESCRT-I assembly or is ESCRT-independent unclear","Direct biochemical mechanism preventing K48 ubiquitination not defined"]},{"year":2024,"claim":"Identified VPS37C as an intracellular binding target of hydroxychloroquine, raising a potential pharmacological link.","evidence":"POST-IT non-diffusive proximity tagging in live cells","pmids":["39728918"],"confidence":"Low","gaps":["Functional consequence of the hydroxychloroquine–VPS37C interaction not characterized","Binding not orthogonally validated"]},{"year":null,"claim":"How VPS37C isoform-specific ESCRT-I complexes are selected for distinct cargoes, and how the ESCRT and EKLF-stabilizing roles are integrated, remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structural model of VPS37C within ESCRT-I","Endogenous physiological cargoes and tissue-specific roles undefined","Mechanistic link between ESCRT membership and transcription-factor stabilization unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[0,4]},{"term_id":"GO:0005198","term_label":"structural molecule activity","supporting_discovery_ids":[0,6]}],"localization":[{"term_id":"GO:0005768","term_label":"endosome","supporting_discovery_ids":[0]},{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[0,1]}],"pathway":[{"term_id":"R-HSA-5653656","term_label":"Vesicle-mediated transport","supporting_discovery_ids":[0,1]}],"complexes":["ESCRT-I","ESCRT-I/ALIX/ALG-2"],"partners":["TSG101","VPS28","HRS","TBK1","ALG-2","ALIX","CDIP1","KLF1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"A5D8V6","full_name":"Vacuolar protein sorting-associated protein 37C","aliases":["ESCRT-I complex subunit VPS37C"],"length_aa":355,"mass_kda":38.7,"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/A5D8V6/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/VPS37C","classification":"Not Classified","n_dependent_lines":131,"n_total_lines":1208,"dependency_fraction":0.10844370860927152},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"TSG101","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/VPS37C","total_profiled":1310},"omim":[{"mim_id":"610038","title":"VPS37C SUBUNIT OF ESCRT-I; VPS37C","url":"https://www.omim.org/entry/610038"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Enhanced","locations":[{"location":"Nucleoplasm","reliability":"Enhanced"},{"location":"Vesicles","reliability":"Enhanced"},{"location":"Golgi apparatus","reliability":"Additional"},{"location":"Primary cilium","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/VPS37C"},"hgnc":{"alias_symbol":["FLJ20847"],"prev_symbol":[]},"alphafold":{"accession":"A5D8V6","domains":[{"cath_id":"1.20.5","chopping":"10-88","consensus_level":"medium","plddt":95.0587,"start":10,"end":88},{"cath_id":"1.10.287","chopping":"97-159","consensus_level":"medium","plddt":96.8029,"start":97,"end":159}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/A5D8V6","model_url":"https://alphafold.ebi.ac.uk/files/AF-A5D8V6-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-A5D8V6-F1-predicted_aligned_error_v6.png","plddt_mean":67.62},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=VPS37C","jax_strain_url":"https://www.jax.org/strain/search?query=VPS37C"},"sequence":{"accession":"A5D8V6","fasta_url":"https://rest.uniprot.org/uniprotkb/A5D8V6.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/A5D8V6/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/A5D8V6"}},"corpus_meta":[{"pmid":"21757351","id":"PMC_21757351","title":"UBAP1 is a component of an endosome-specific ESCRT-I complex that is essential for MVB sorting.","date":"2011","source":"Current biology : CB","url":"https://pubmed.ncbi.nlm.nih.gov/21757351","citation_count":110,"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":"18723511","id":"PMC_18723511","title":"Avian sarcoma virus and human immunodeficiency virus, type 1 use different subsets of ESCRT proteins to facilitate the budding process.","date":"2008","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/18723511","citation_count":49,"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 science","url":"https://pubmed.ncbi.nlm.nih.gov/33419951","citation_count":25,"is_preprint":false},{"pmid":"37255317","id":"PMC_37255317","title":"Diagnosis of Multisystem Inflammatory Syndrome in Children by a Whole-Blood Transcriptional Signature.","date":"2023","source":"Journal of the Pediatric Infectious Diseases Society","url":"https://pubmed.ncbi.nlm.nih.gov/37255317","citation_count":17,"is_preprint":false},{"pmid":"33503978","id":"PMC_33503978","title":"The Novel ALG-2 Target Protein CDIP1 Promotes Cell Death by Interacting with ESCRT-I and VAPA/B.","date":"2021","source":"International 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Progression.","date":"2024","source":"Journal of the American Heart Association","url":"https://pubmed.ncbi.nlm.nih.gov/39655704","citation_count":4,"is_preprint":false},{"pmid":"34854013","id":"PMC_34854013","title":"Development of a custom next-generation sequencing panel for the determination of bladder cancer risk in a Tunisian cohort.","date":"2021","source":"Molecular biology reports","url":"https://pubmed.ncbi.nlm.nih.gov/34854013","citation_count":4,"is_preprint":false},{"pmid":"39890050","id":"PMC_39890050","title":"Corneal stromal cells from patients with keratoconus exhibit alterations in the ESCRT-dependent machinery responsible for multivesicular body formation.","date":"2025","source":"Experimental eye research","url":"https://pubmed.ncbi.nlm.nih.gov/39890050","citation_count":4,"is_preprint":false},{"pmid":"39728918","id":"PMC_39728918","title":"Target protein identification in live cells and organisms with a non-diffusive proximity tagging 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VPS37C also binds the class E VPS factor HRS. VPS37C is recruited to aberrant endosomes induced by overexpression of TSG101, HRS, or dominant-negative VPS4. Depletion of VPS37C inhibits PTAP-mediated (ESCRT-I-dependent) retroviral budding but not PPPY-mediated (ESCRT-I-independent) budding. Direct fusion of VPS37C to HIV-1 Gag rescues budding of a PTAP-deleted Gag.\",\n      \"method\": \"Yeast two-hybrid screen, co-immunoprecipitation, subcellular localization by overexpression/dominant-negative, siRNA depletion with viral budding assay, Gag-VPS37C fusion rescue experiment\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (Y2H, Co-IP, localization, depletion phenotype, fusion rescue) in a single focused study establishing ESCRT-I membership and function\",\n      \"pmids\": [\"15509564\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"VPS37C (ESCRT-I) is required for HIV-1 Gag PTAP-dependent budding but not for ASV Gag PPPY-dependent budding: endogenous VPS37C depletion blocks HIV-1 release while having little effect on ASV release, demonstrating that ASV and HIV-1 utilize different ESCRT-I requirements.\",\n      \"method\": \"siRNA depletion of endogenous VPS37C combined with viral particle release assays; Gag-ESCRT fusion rescue experiments\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal depletion and rescue experiments across two viral systems, consistent with and extending prior work\",\n      \"pmids\": [\"18723511\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"VPS37C-containing ESCRT-I is distinct from a UBAP1/VPS37A-containing endosome-specific ESCRT-I complex: UBAP1 associates with a fraction of TSG101 that also contains VPS37A but not VPS37C, indicating that VPS37C defines a separate ESCRT-I complex isoform.\",\n      \"method\": \"Co-immunoprecipitation, siRNA knockdown, endosomal sorting assays (EGFR degradation)\",\n      \"journal\": \"Current biology : CB\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP demonstrating exclusion of VPS37C from the UBAP1/VPS37A complex, replicated with functional assays\",\n      \"pmids\": [\"21757351\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"TBK1 directly interacts with VPS37C and phosphorylates it, attenuating PTAP-dependent retroviral budding. TBK1 overexpression reduces HIV-1 pseudovirus release; TBK1 depletion or kinase-inactive TBK1 (K38A) enhances PTAP-dependent budding. This effect is independent of type I interferon signaling.\",\n      \"method\": \"Co-immunoprecipitation (TBK1–VPS37C interaction), shRNA knockdown, TBK1 kinase-dead mutant overexpression, viral budding assays in TBK1-knockout MEFs\",\n      \"journal\": \"Journal of immunology (Baltimore, Md. : 1950)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP interaction plus kinase-dead mutant phenotype and KO MEF experiments from a single lab; phosphorylation of VPS37C inferred but in vitro kinase assay not explicitly described in abstract\",\n      \"pmids\": [\"21270402\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"VPS37C-containing ESCRT-I interacts with ALG-2 more strongly than TSG101 does. ALG-2 acts as a Ca2+-dependent adaptor bridging ALIX and ESCRT-I (including VPS37B- and VPS37C-containing complexes) to form a ternary ESCRT-I/ALIX/ALG-2 complex.\",\n      \"method\": \"Far-Western blot with biotin-labeled ALG-2 probe, pulldown assay of recombinant ESCRT-I complexes expressed 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 reconstitution with purified proteins plus cell-based pulldown; single lab with two orthogonal methods\",\n      \"pmids\": [\"23924735\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"CDIP1 preferentially associates with ESCRT-I containing VPS37B or VPS37C (over other VPS37 isoforms), in part through the adaptor function of ALG-2. Co-expression of ALG-2 and VPS37C-containing ESCRT-I enhances CDIP1-induced caspase-3/7-mediated cell death.\",\n      \"method\": \"Co-immunoprecipitation of GFP-CDIP1 with ESCRT-I isoforms, caspase-3/7 cell death assay with overexpression in HEK293 cells\",\n      \"journal\": \"International journal of molecular sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — single Co-IP with isoform specificity plus functional cell death assay; single lab\",\n      \"pmids\": [\"33503978\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Concurrent knockdown of VPS37A, VPS37B, and VPS37C destabilizes ESCRT-I and triggers p21/CDKN1A-mediated inhibition of cell proliferation and NF-κB-driven sterile inflammatory response. VPS37C co-silencing potentiates these responses induced by VPS37A/B double knockdown, indicating non-redundant roles of VPS37C within ESCRT-I.\",\n      \"method\": \"siRNA knockdown (individual and combined), transcriptomic profiling, Western blot for ESCRT-I stability, NF-κB reporter and p21 assessment\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic epistasis by combinatorial knockdown with defined transcriptional phenotype; single lab with multiple readouts\",\n      \"pmids\": [\"33419951\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"VPS37C interacts with EKLF/KLF1 transcription factor and prevents K48-linked polyubiquitination of EKLF, thereby blocking proteasome-mediated EKLF degradation. VPS37C overexpression promotes erythroid differentiation of MEL cells (increased EKLF target gene expression and benzidine-positive cells); VPS37C knockdown inhibits differentiation, and EKLF re-expression in VPS37C-knockdown cells restores erythroid gene expression and hemoglobin production.\",\n      \"method\": \"Co-immunoprecipitation (VPS37C–EKLF interaction), ubiquitination assay (K48-linkage specific), overexpression and siRNA knockdown in MEL cells with HMBA-induced differentiation, rescue experiment by EKLF re-expression\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP plus ubiquitination assay plus loss-of-function/rescue in a single lab with multiple orthogonal methods\",\n      \"pmids\": [\"37307706\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"VPS37C was identified as a novel intracellular binding target of hydroxychloroquine using the POST-IT non-diffusive proximity tagging system in live cells.\",\n      \"method\": \"POST-IT proximity tagging (engineered PafA-HaloTag fusion transferring Pup to proximal proteins upon small-molecule binding) in live cells\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single novel method from a single lab; mechanistic consequences of VPS37C–hydroxychloroquine interaction not characterized in the abstract\",\n      \"pmids\": [\"39728918\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"VPS37C is a core subunit of mammalian ESCRT-I that assembles with TSG101 and VPS28 into a distinct complex isoform (separate from the UBAP1/VPS37A-containing endosome-specific ESCRT-I); it participates in PTAP-dependent retroviral budding, is phosphorylated by TBK1 to attenuate this budding, bridges ESCRT-I to ALIX via Ca2+-dependent ALG-2 adaptor function, stabilizes the EKLF transcription factor against K48-linked ubiquitin–proteasome degradation to promote erythroid differentiation, and contributes to overall ESCRT-I structural integrity such that its depletion—especially combined with VPS37A/B depletion—triggers NF-κB-driven inflammatory stress responses and cell-cycle arrest.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"VPS37C is a core subunit of mammalian ESCRT-I that assembles with TSG101 and VPS28 into a ternary complex and also binds the class E VPS factor HRS, defining a complex isoform distinct from the endosome-specific UBAP1/VPS37A-containing ESCRT-I [#0, #2]. In this capacity it is required for PTAP-dependent (ESCRT-I-dependent) retroviral budding but dispensable for PPPY-dependent budding, as shown by depletion phenotypes and rescue when VPS37C is fused directly to a PTAP-deleted HIV-1 Gag [#0, #1]. This budding function is negatively regulated by TBK1, which directly binds and phosphorylates VPS37C to attenuate PTAP-dependent release independently of type I interferon signaling [#3]. VPS37C-containing ESCRT-I is bridged to the accessory factor ALIX through the Ca2+-dependent adaptor ALG-2, forming an ESCRT-I/ALIX/ALG-2 ternary complex, and this same ALG-2 adaptor links VPS37C-containing ESCRT-I to CDIP1 to promote caspase-3/7-mediated cell death [#4, #5]. VPS37C contributes non-redundantly to overall ESCRT-I structural integrity: combined depletion of VPS37A/B/C destabilizes the complex and triggers p21/CDKN1A-mediated proliferation arrest and NF-\\u03baB-driven sterile inflammatory responses [#6]. Beyond its ESCRT role, VPS37C stabilizes the EKLF/KLF1 transcription factor by blocking its K48-linked polyubiquitination and proteasomal degradation, thereby promoting erythroid differentiation [#7].\",\n  \"teleology\": [\n    {\n      \"year\": 2004,\n      \"claim\": \"Established VPS37C as a bona fide ESCRT-I subunit and connected it functionally to ESCRT-dependent membrane budding, answering whether it is a structural component versus a peripheral factor.\",\n      \"evidence\": \"Yeast two-hybrid, Co-IP forming a TSG101/VPS28 ternary complex, localization to aberrant endosomes, siRNA depletion blocking PTAP-dependent budding, and Gag-VPS37C fusion rescue\",\n      \"pmids\": [\"15509564\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Stoichiometry and structural organization within ESCRT-I not resolved\", \"Endogenous cargo sorting role distinct from viral budding not defined\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Clarified that PTAP- versus PPPY-dependent viral budding pathways have divergent ESCRT-I requirements, with VPS37C specifically needed for HIV-1 but not ASV release.\",\n      \"evidence\": \"siRNA depletion of endogenous VPS37C with viral particle release assays across two retroviral systems plus fusion rescue\",\n      \"pmids\": [\"18723511\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular basis for late-domain selectivity not detailed\", \"Role of other VPS37 isoforms in the same assays not contrasted\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Demonstrated that VPS37C defines a distinct ESCRT-I isoform separate from the UBAP1/VPS37A endosomal complex, addressing whether VPS37 paralogs are interchangeable.\",\n      \"evidence\": \"Reciprocal Co-IP showing UBAP1 associates with VPS37A but not VPS37C, with EGFR-degradation endosomal sorting assays\",\n      \"pmids\": [\"21757351\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Cellular contexts that select one isoform over another unknown\", \"Functional consequences of isoform identity for distinct cargoes not mapped\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Identified TBK1 as a direct regulator of VPS37C, establishing a kinase-mediated brake on ESCRT-dependent budding outside of interferon signaling.\",\n      \"evidence\": \"Co-IP of TBK1\\u2013VPS37C, shRNA knockdown, kinase-dead K38A mutant, and budding assays in TBK1-knockout MEFs\",\n      \"pmids\": [\"21270402\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"In vitro kinase assay confirming direct phosphorylation not described\", \"Phosphorylation site(s) on VPS37C not mapped\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Defined how VPS37C-containing ESCRT-I couples to the ALIX branch, showing ALG-2 acts as a Ca2+-dependent bridge into an ESCRT-I/ALIX/ALG-2 ternary complex.\",\n      \"evidence\": \"Far-Western with ALG-2 probe, pulldown of recombinant ESCRT-I complexes, and in vitro binding with purified proteins\",\n      \"pmids\": [\"23924735\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Physiological process requiring this Ca2+-dependent bridge not established\", \"Single-lab in vitro reconstitution\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Linked VPS37C-containing ESCRT-I to programmed cell death by showing isoform-selective association with CDIP1 via ALG-2 that potentiates caspase activation.\",\n      \"evidence\": \"Co-IP of GFP-CDIP1 with ESCRT-I isoforms and caspase-3/7 cell death assays in HEK293 cells\",\n      \"pmids\": [\"33503978\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Endogenous (non-overexpression) relevance not shown\", \"Mechanism connecting ESCRT-I/CDIP1 to caspase activation unresolved\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Showed VPS37C contributes non-redundantly to ESCRT-I integrity, with combinatorial loss triggering cell-cycle arrest and sterile inflammation.\",\n      \"evidence\": \"Individual and combined siRNA knockdown, transcriptomics, ESCRT-I stability blots, NF-\\u03baB reporter and p21 readouts\",\n      \"pmids\": [\"33419951\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct trigger linking ESCRT-I destabilization to NF-\\u03baB not identified\", \"Single-knockdown VPS37C phenotype relatively mild\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Revealed a non-ESCRT function in which VPS37C stabilizes the EKLF transcription factor to drive erythroid differentiation, expanding its role beyond membrane trafficking.\",\n      \"evidence\": \"Co-IP, K48-linkage-specific ubiquitination assay, overexpression/knockdown in MEL cells with induced differentiation, and EKLF re-expression rescue\",\n      \"pmids\": [\"37307706\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether stabilization requires ESCRT-I assembly or is ESCRT-independent unclear\", \"Direct biochemical mechanism preventing K48 ubiquitination not defined\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Identified VPS37C as an intracellular binding target of hydroxychloroquine, raising a potential pharmacological link.\",\n      \"evidence\": \"POST-IT non-diffusive proximity tagging in live cells\",\n      \"pmids\": [\"39728918\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Functional consequence of the hydroxychloroquine\\u2013VPS37C interaction not characterized\", \"Binding not orthogonally validated\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How VPS37C isoform-specific ESCRT-I complexes are selected for distinct cargoes, and how the ESCRT and EKLF-stabilizing roles are integrated, remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structural model of VPS37C within ESCRT-I\", \"Endogenous physiological cargoes and tissue-specific roles undefined\", \"Mechanistic link between ESCRT membership and transcription-factor stabilization unknown\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [0, 4]},\n      {\"term_id\": \"GO:0005198\", \"supporting_discovery_ids\": [0, 6]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005768\", \"supporting_discovery_ids\": [0]},\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [0, 1]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-5653656\", \"supporting_discovery_ids\": [0, 1]}\n    ],\n    \"complexes\": [\"ESCRT-I\", \"ESCRT-I/ALIX/ALG-2\"],\n    \"partners\": [\"TSG101\", \"VPS28\", \"HRS\", \"TBK1\", \"ALG-2\", \"ALIX\", \"CDIP1\", \"KLF1\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}