{"gene":"VPS37A","run_date":"2026-04-28T23:00:23","timeline":{"discoveries":[{"year":2004,"finding":"VPS37A (HCRP1) is a subunit of mammalian ESCRT-I complex, interacting with Tsg101, hVps28, and upstream regulator Hrs. The interaction with Tsg101 is mediated by VPS37A's mod(r) domain. VPS37A co-fractionates with Tsg101 and hVps28 by size exclusion chromatography and colocalizes with hVps28 on LAMP1-positive endosomes. siRNA depletion of VPS37A strongly retards EGF receptor degradation, establishing its essential role in lysosomal sorting of EGF receptors.","method":"Co-immunoprecipitation, size exclusion chromatography, siRNA knockdown, colocalization by immunofluorescence, EGF receptor degradation assay","journal":"Molecular biology of the cell","confidence":"High","confidence_rationale":"Tier 2 — reciprocal Co-IP, fractionation, colocalization, and functional KD phenotype; foundational paper with 137 citations","pmids":["15240819"],"is_preprint":false},{"year":2019,"finding":"VPS37A is required for phagophore closure during autophagy. VPS37A localizes on the phagophore through its N-terminal ubiquitin E2 variant (UEV) domain. This UEV domain is required for autophagosome completion but is dispensable for ESCRT-I complex formation and EGFR degradation via the MVB pathway. Loss of VPS37A abrogates phagophore recruitment of ESCRT-I subunit VPS28 and ESCRT-III subunit CHMP2A, placing VPS37A upstream of ESCRT-III in phagophore closure.","method":"Genome-wide CRISPR screen (FACS-based HaloTag-LC3 autophagosome completion assay), domain deletion/mutagenesis, siRNA knockdown, live imaging, epistasis analysis with CHMP2A and VPS4","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 1-2 — genome-wide unbiased screen, domain mutagenesis, epistasis with multiple ESCRT components, 97 citations","pmids":["31519728"],"is_preprint":false},{"year":2022,"finding":"Hepatocyte-specific knockdown of Vps37a causes accumulation of glucagon receptor (Gcgr) in endosomes, resulting in overactivation of cAMP/PKA/p-Creb signaling to gluconeogenesis without affecting β-oxidation. Shifting the receptor back to the plasma membrane rescues differential signaling, demonstrating that Vps37a controls the spatiotemporal localization of Gcgr to uncouple glucose production from lipid metabolism.","method":"Cy5-glucagon agonist trafficking assay, hepatocyte-specific siRNA knockdown in mice, cAMP/PKA/p-Creb signaling measurements, receptor re-localization rescue experiment","journal":"Cell metabolism","confidence":"High","confidence_rationale":"Tier 2 — direct receptor localization assay, signaling pathway readout, in vivo knockdown with rescue, multiple orthogonal methods","pmids":["36243006"],"is_preprint":false},{"year":2024,"finding":"The VPS37A ubiquitin E2 variant-like (UEVL) domain (β strands 43-139) is specifically required for phagophore closure and bulk autophagic flux. The UEVL mutation (Δ43-139) impairs autophagosome closure without disrupting ESCRT-I complex assembly or endosomal function. Loss of UEVL function leads to active TBK1 accumulation on phagophores (detected by LC3 proximity proteomics), resulting in increased p62 phosphorylation and inclusion body formation.","method":"Knock-in mouse model with UEVL deletion, LC3 proximity proteomics (BioID), autophagic flux assays, p62/ubiquitin accumulation analysis, TBK1 activity measurements","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 1-2 — in vivo knock-in mutagenesis, proximity proteomics, multiple orthogonal readouts separating ESCRT-I vs. autophagy functions","pmids":["39607828"],"is_preprint":false},{"year":2025,"finding":"VPS37A directs TNFR1 to lysosomal degradation via the autophagy-lysosomal pathway, thereby suppressing NF-κB nuclear translocation and transcriptional activity under metabolic stress in colorectal cancer cells.","method":"VPS37A overexpression, RNA sequencing, NF-κB luciferase reporter assay, lysosomal inhibition experiments, xenograft assays","journal":"Oncology research","confidence":"Medium","confidence_rationale":"Tier 2 — multiple functional assays and reporter assays, single lab study","pmids":["40746890"],"is_preprint":false},{"year":2020,"finding":"HCRP-1/VPS37A depletion induces Src and FAK phosphorylation in prostate cancer cells, promoting cell migration, invasion, and angiogenesis; these effects are reversed by Src inhibitor PP2 or FAK inhibitor, placing VPS37A upstream of Src/FAK signaling. Note: the original research paper (PMID 31929761) was subsequently retracted (PMID 34803514).","method":"Co-immunoprecipitation, western blot, transwell/tube formation assays, pharmacological inhibition with PP2 and FAK inhibitor — RETRACTED","journal":"International journal of biological sciences","confidence":"Low","confidence_rationale":"Tier 3 — single Co-IP/western blot; paper retracted","pmids":["31929761","34803514"],"is_preprint":false},{"year":2019,"finding":"In MLKL-deficient colorectal cancer cells, autophagy becomes critically dependent on VPS37A, and p38 MAPK activation prevents VPS37A from supporting autophagy, triggering parthanatos cell death.","method":"MLKL gene knockout, VPS37A functional dependency assay, p38 MAPK inhibition/activation, cell death assays","journal":"bioRxiv","confidence":"Low","confidence_rationale":"Tier 3 — genetic epistasis in cell lines, preprint, single lab","pmids":[],"is_preprint":true}],"current_model":"VPS37A is a subunit of the mammalian ESCRT-I complex that uses its mod(r) domain to interact with Tsg101 and hVps28 and localizes to late endosomes to drive lysosomal degradation of ubiquitinated membrane receptors (e.g., EGFR, TNFR1, glucagon receptor); additionally, its N-terminal ubiquitin E2 variant-like (UEVL) domain directs VPS37A to the phagophore independently of ESCRT-I assembly, where it recruits VPS28 and CHMP2A to coordinate ESCRT-III–VPS4-dependent phagophore closure during autophagy, with loss of UEVL function causing TBK1 accumulation on unclosed phagophores and enhanced p62 phosphorylation and inclusion formation."},"narrative":{"teleology":[{"year":2004,"claim":"Identification of VPS37A as a bona fide ESCRT-I subunit resolved how a then-uncharacterized protein (HCRP1) links the upstream Hrs/STAM machinery to the Tsg101–VPS28 core complex and established its requirement for lysosomal degradation of EGF receptors.","evidence":"Reciprocal co-IP, size-exclusion co-fractionation, colocalization on LAMP1-positive endosomes, and siRNA knockdown showing impaired EGFR degradation in human cells","pmids":["15240819"],"confidence":"High","gaps":["Structural basis of the mod(r)-mediated interaction with Tsg101 not resolved","Whether VPS37A has functions beyond the MVB pathway was unknown","No information on receptor specificity beyond EGFR"]},{"year":2019,"claim":"A genome-wide CRISPR screen revealed that VPS37A's role extends beyond endosomal sorting to phagophore closure during autophagy, and domain dissection showed that the N-terminal UEV domain is required for phagophore localization and ESCRT-III recruitment but dispensable for ESCRT-I complex formation.","evidence":"FACS-based HaloTag-LC3 autophagosome completion screen, UEV deletion mutants, epistasis with CHMP2A and VPS4, live imaging in human cells","pmids":["31519728"],"confidence":"High","gaps":["Identity of the phagophore receptor or lipid determinant recognized by the UEV domain unknown","Downstream signaling consequences of failed phagophore closure not addressed"]},{"year":2022,"claim":"Extending VPS37A's endosomal function to metabolic physiology, hepatocyte-specific knockdown demonstrated that VPS37A controls the spatiotemporal localization of the glucagon receptor, uncoupling gluconeogenesis from β-oxidation in vivo.","evidence":"Cy5-glucagon trafficking, hepatocyte-specific siRNA in mice, cAMP/PKA/p-CREB signaling readouts, receptor re-localization rescue","pmids":["36243006"],"confidence":"High","gaps":["Whether VPS37A similarly regulates other hepatocyte GPCRs is untested","Mechanism by which glucagon receptor is preferentially retained in endosomes upon VPS37A loss not defined"]},{"year":2024,"claim":"An in vivo knock-in model pinpointed the UEVL domain (β-strands 43–139) as the autophagy-specific module of VPS37A and revealed that failed phagophore closure leads to TBK1 accumulation on open phagophores, enhanced p62 phosphorylation, and inclusion body formation—linking ESCRT-mediated membrane sealing to innate immune kinase signaling.","evidence":"UEVL-deletion knock-in mice, LC3 BioID proximity proteomics, autophagic flux and p62/ubiquitin accumulation assays, TBK1 activity measurements","pmids":["39607828"],"confidence":"High","gaps":["How TBK1 is activated by open phagophores is mechanistically unclear","Whether the inclusion body phenotype leads to neurodegeneration or tissue pathology in vivo not established","No structural model of UEVL domain at atomic resolution"]},{"year":2025,"claim":"VPS37A was shown to direct TNFR1 to lysosomal degradation via the autophagy-lysosomal pathway, suppressing NF-κB signaling in colorectal cancer cells under metabolic stress, broadening the receptor repertoire controlled by VPS37A.","evidence":"VPS37A overexpression, RNA-seq, NF-κB luciferase reporter, lysosomal inhibition, xenograft assays","pmids":["40746890"],"confidence":"Medium","gaps":["Whether TNFR1 degradation uses the MVB or autophagy arm of VPS37A function not distinguished","Single-lab study; awaits independent confirmation"]},{"year":null,"claim":"The phagophore-targeting mechanism of the UEVL domain remains unresolved: neither the membrane determinant (lipid species or protein receptor) recognized by the UEVL domain nor the structural basis for selective phagophore versus endosome engagement has been identified.","evidence":"","pmids":[],"confidence":"High","gaps":["No binding partner or lipid ligand identified for the UEVL domain on the phagophore","No high-resolution structure of VPS37A UEVL domain available","In vivo physiological consequences of UEVL loss (beyond TBK1/p62) in disease models not characterized"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[0,1,3]}],"localization":[{"term_id":"GO:0005768","term_label":"endosome","supporting_discovery_ids":[0,2]},{"term_id":"GO:0031410","term_label":"cytoplasmic vesicle","supporting_discovery_ids":[0,1,3]},{"term_id":"GO:0005764","term_label":"lysosome","supporting_discovery_ids":[0,2,4]}],"pathway":[{"term_id":"R-HSA-5653656","term_label":"Vesicle-mediated transport","supporting_discovery_ids":[0,2]},{"term_id":"R-HSA-9612973","term_label":"Autophagy","supporting_discovery_ids":[1,3,4]}],"complexes":["ESCRT-I"],"partners":["TSG101","VPS28","HGS","CHMP2A"],"other_free_text":[]},"mechanistic_narrative":"VPS37A is a core subunit of the mammalian ESCRT-I complex that functions in both endosomal sorting and autophagosome biogenesis. Through its mod(r) domain, VPS37A assembles with Tsg101 and VPS28 on late endosomes to drive lysosomal degradation of ubiquitinated membrane receptors including EGFR, TNFR1, and the glucagon receptor, with hepatocyte-specific loss causing endosomal accumulation of the glucagon receptor and overactivation of cAMP/PKA/CREB-dependent gluconeogenesis [PMID:15240819, PMID:36243006, PMID:40746890]. Independently of its ESCRT-I assembly function, VPS37A uses its N-terminal ubiquitin E2 variant-like (UEVL) domain to localize to the phagophore, where it recruits VPS28 and the ESCRT-III subunit CHMP2A to mediate VPS4-dependent phagophore closure; loss of UEVL function blocks autophagosome completion, causes TBK1 accumulation on unclosed phagophores, and drives p62 hyperphosphorylation and inclusion body formation [PMID:31519728, PMID:39607828]."},"prefetch_data":{"uniprot":{"accession":"Q8NEZ2","full_name":"Vacuolar protein sorting-associated protein 37A","aliases":["ESCRT-I complex subunit VPS37A","Hepatocellular carcinoma-related protein 1"],"length_aa":397,"mass_kda":44.3,"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; Nucleus","url":"https://www.uniprot.org/uniprotkb/Q8NEZ2/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/VPS37A","classification":"Not Classified","n_dependent_lines":555,"n_total_lines":1208,"dependency_fraction":0.4594370860927152},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"TSG101","stoichiometry":10.0},{"gene":"COPA","stoichiometry":0.2},{"gene":"VPS28","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/VPS37A","total_profiled":1310},"omim":[{"mim_id":"621454","title":"MULTIVESICULAR BODY SUBUNIT 12B; MVB12B","url":"https://www.omim.org/entry/621454"},{"mim_id":"621453","title":"MULTIVESICULAR BODY SUBUNIT 12A; MVB12A","url":"https://www.omim.org/entry/621453"},{"mim_id":"614898","title":"SPASTIC PARAPLEGIA 53, AUTOSOMAL RECESSIVE; SPG53","url":"https://www.omim.org/entry/614898"},{"mim_id":"609927","title":"VPS37A SUBUNIT OF ESCRIT-I; VPS37A","url":"https://www.omim.org/entry/609927"},{"mim_id":"609787","title":"UBIQUITIN-ASSOCIATED PROTEIN 1; UBAP1","url":"https://www.omim.org/entry/609787"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Vesicles","reliability":"Approved"},{"location":"Centrosome","reliability":"Approved"},{"location":"Acrosome","reliability":"Approved"},{"location":"Flagellar centriole","reliability":"Approved"},{"location":"Nucleoplasm","reliability":"Additional"},{"location":"Cytosol","reliability":"Additional"},{"location":"Equatorial segment","reliability":"Additional"},{"location":"Perinuclear theca","reliability":"Additional"},{"location":"Mid piece","reliability":"Additional"},{"location":"Principal piece","reliability":"Additional"},{"location":"End piece","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/VPS37A"},"hgnc":{"alias_symbol":["FLJ32642","HCRP1","SPG53"],"prev_symbol":["PQBP2"]},"alphafold":{"accession":"Q8NEZ2","domains":[{"cath_id":"3.10.110.10","chopping":"25-131","consensus_level":"high","plddt":93.275,"start":25,"end":131},{"cath_id":"1.20.5","chopping":"248-314","consensus_level":"high","plddt":94.1566,"start":248,"end":314},{"cath_id":"1.20.58","chopping":"327-395","consensus_level":"high","plddt":92.3267,"start":327,"end":395}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q8NEZ2","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q8NEZ2-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q8NEZ2-F1-predicted_aligned_error_v6.png","plddt_mean":76.12},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=VPS37A","jax_strain_url":"https://www.jax.org/strain/search?query=VPS37A"},"sequence":{"accession":"Q8NEZ2","fasta_url":"https://rest.uniprot.org/uniprotkb/Q8NEZ2.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q8NEZ2/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q8NEZ2"}},"corpus_meta":[{"pmid":"15240819","id":"PMC_15240819","title":"The growth-regulatory protein HCRP1/hVps37A is a subunit of mammalian ESCRT-I and mediates receptor down-regulation.","date":"2004","source":"Molecular biology of the cell","url":"https://pubmed.ncbi.nlm.nih.gov/15240819","citation_count":137,"is_preprint":false},{"pmid":"31519728","id":"PMC_31519728","title":"VPS37A directs ESCRT recruitment for phagophore closure.","date":"2019","source":"The Journal of cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/31519728","citation_count":97,"is_preprint":false},{"pmid":"14623289","id":"PMC_14623289","title":"HCRP1, a novel gene that is downregulated in hepatocellular carcinoma, encodes a growth-inhibitory protein.","date":"2003","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/14623289","citation_count":64,"is_preprint":false},{"pmid":"22717650","id":"PMC_22717650","title":"A founder mutation in Vps37A causes autosomal recessive complex hereditary spastic paraparesis.","date":"2012","source":"Journal of medical genetics","url":"https://pubmed.ncbi.nlm.nih.gov/22717650","citation_count":59,"is_preprint":false},{"pmid":"36243006","id":"PMC_36243006","title":"Vps37a regulates hepatic glucose production by controlling glucagon receptor localization to endosomes.","date":"2022","source":"Cell metabolism","url":"https://pubmed.ncbi.nlm.nih.gov/36243006","citation_count":19,"is_preprint":false},{"pmid":"28122307","id":"PMC_28122307","title":"HCRP1 downregulation promotes hepatocellular carcinoma cell migration and invasion through the induction of EGFR activation and epithelial-mesenchymal transition.","date":"2017","source":"Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie","url":"https://pubmed.ncbi.nlm.nih.gov/28122307","citation_count":18,"is_preprint":false},{"pmid":"27311861","id":"PMC_27311861","title":"Decreased HCRP1 promotes breast cancer metastasis by enhancing EGFR phosphorylation.","date":"2016","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/27311861","citation_count":15,"is_preprint":false},{"pmid":"27739029","id":"PMC_27739029","title":"HCRP1 is downregulated in non-small cell lung cancer and regulates proliferation, invasion, and drug resistance.","date":"2016","source":"Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine","url":"https://pubmed.ncbi.nlm.nih.gov/27739029","citation_count":13,"is_preprint":false},{"pmid":"31152734","id":"PMC_31152734","title":"HCRP1 inhibits cell proliferation and invasion and promotes chemosensitivity in esophageal squamous cell carcinoma.","date":"2019","source":"Chemico-biological interactions","url":"https://pubmed.ncbi.nlm.nih.gov/31152734","citation_count":12,"is_preprint":false},{"pmid":"28350062","id":"PMC_28350062","title":"HCRP1 inhibits TGF-β induced epithelial-mesenchymal transition in hepatocellular carcinoma.","date":"2017","source":"International journal of oncology","url":"https://pubmed.ncbi.nlm.nih.gov/28350062","citation_count":12,"is_preprint":false},{"pmid":"28458158","id":"PMC_28458158","title":"HCRP1 regulates proliferation, invasion, and drug resistance via EGFR signaling in prostate cancer.","date":"2017","source":"Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie","url":"https://pubmed.ncbi.nlm.nih.gov/28458158","citation_count":9,"is_preprint":false},{"pmid":"31929761","id":"PMC_31929761","title":"HCRP-1 regulates cell migration, invasion and angiogenesis via Src/ FAK signaling in human prostate cancer.","date":"2020","source":"International journal of biological sciences","url":"https://pubmed.ncbi.nlm.nih.gov/31929761","citation_count":7,"is_preprint":false},{"pmid":"28826094","id":"PMC_28826094","title":"Up-regulation of HCRP1 inhibits proliferation and invasion in glioma cells via suppressing the ERK and AKT signaling pathways.","date":"2017","source":"Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie","url":"https://pubmed.ncbi.nlm.nih.gov/28826094","citation_count":5,"is_preprint":false},{"pmid":"39607828","id":"PMC_39607828","title":"Unveiling the physiological impact of ESCRT-dependent autophagosome closure by targeting the VPS37A ubiquitin E2 variant-like domain.","date":"2024","source":"Cell reports","url":"https://pubmed.ncbi.nlm.nih.gov/39607828","citation_count":3,"is_preprint":false},{"pmid":"36276496","id":"PMC_36276496","title":"HCRP-1 alleviates the malignant phenotype and angiogenesis of oral squamous cell carcinoma cells via the downregulation of the EGFR/STAT3 signaling pathway.","date":"2022","source":"Oncology letters","url":"https://pubmed.ncbi.nlm.nih.gov/36276496","citation_count":3,"is_preprint":false},{"pmid":"31949663","id":"PMC_31949663","title":"HCRP1, ID4 and Glypican-3: an optimal panel of biomarkers for diagnosis of hepatocellular carcinoma.","date":"2018","source":"International journal of clinical and experimental pathology","url":"https://pubmed.ncbi.nlm.nih.gov/31949663","citation_count":2,"is_preprint":false},{"pmid":"40746890","id":"PMC_40746890","title":"VPS37A Activates the Autophagy-Lysosomal Pathway for TNFR1 Degradation and Induces NF-κB-Regulated Cell Death under Metabolic Stress in Colorectal Cancer.","date":"2025","source":"Oncology research","url":"https://pubmed.ncbi.nlm.nih.gov/40746890","citation_count":1,"is_preprint":false},{"pmid":"34803514","id":"PMC_34803514","title":"Retraction: HCRP-1 regulates cell migration, invasion and angiogenesis via Src/ FAK signaling in human prostate cancer.","date":"2021","source":"International journal of biological sciences","url":"https://pubmed.ncbi.nlm.nih.gov/34803514","citation_count":1,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2024.09.05.611491","title":"Inactivation of necroptosis-promoting protein MLKL creates a therapeutic vulnerability in colorectal cancer cells","date":"2024-09-06","source":"bioRxiv","url":"https://doi.org/10.1101/2024.09.05.611491","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":10604,"output_tokens":2035,"usd":0.031168},"stage2":{"model":"claude-opus-4-6","input_tokens":5306,"output_tokens":1955,"usd":0.113107},"total_usd":0.144275,"stage1_batch_id":"msgbatch_01BparvgRZ9S2LMidvaoo86K","stage2_batch_id":"msgbatch_01NkBfv9SVZWthhS7j6mU6G3","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2004,\n      \"finding\": \"VPS37A (HCRP1) is a subunit of mammalian ESCRT-I complex, interacting with Tsg101, hVps28, and upstream regulator Hrs. The interaction with Tsg101 is mediated by VPS37A's mod(r) domain. VPS37A co-fractionates with Tsg101 and hVps28 by size exclusion chromatography and colocalizes with hVps28 on LAMP1-positive endosomes. siRNA depletion of VPS37A strongly retards EGF receptor degradation, establishing its essential role in lysosomal sorting of EGF receptors.\",\n      \"method\": \"Co-immunoprecipitation, size exclusion chromatography, siRNA knockdown, colocalization by immunofluorescence, EGF receptor degradation assay\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal Co-IP, fractionation, colocalization, and functional KD phenotype; foundational paper with 137 citations\",\n      \"pmids\": [\"15240819\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"VPS37A is required for phagophore closure during autophagy. VPS37A localizes on the phagophore through its N-terminal ubiquitin E2 variant (UEV) domain. This UEV domain is required for autophagosome completion but is dispensable for ESCRT-I complex formation and EGFR degradation via the MVB pathway. Loss of VPS37A abrogates phagophore recruitment of ESCRT-I subunit VPS28 and ESCRT-III subunit CHMP2A, placing VPS37A upstream of ESCRT-III in phagophore closure.\",\n      \"method\": \"Genome-wide CRISPR screen (FACS-based HaloTag-LC3 autophagosome completion assay), domain deletion/mutagenesis, siRNA knockdown, live imaging, epistasis analysis with CHMP2A and VPS4\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — genome-wide unbiased screen, domain mutagenesis, epistasis with multiple ESCRT components, 97 citations\",\n      \"pmids\": [\"31519728\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Hepatocyte-specific knockdown of Vps37a causes accumulation of glucagon receptor (Gcgr) in endosomes, resulting in overactivation of cAMP/PKA/p-Creb signaling to gluconeogenesis without affecting β-oxidation. Shifting the receptor back to the plasma membrane rescues differential signaling, demonstrating that Vps37a controls the spatiotemporal localization of Gcgr to uncouple glucose production from lipid metabolism.\",\n      \"method\": \"Cy5-glucagon agonist trafficking assay, hepatocyte-specific siRNA knockdown in mice, cAMP/PKA/p-Creb signaling measurements, receptor re-localization rescue experiment\",\n      \"journal\": \"Cell metabolism\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — direct receptor localization assay, signaling pathway readout, in vivo knockdown with rescue, multiple orthogonal methods\",\n      \"pmids\": [\"36243006\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"The VPS37A ubiquitin E2 variant-like (UEVL) domain (β strands 43-139) is specifically required for phagophore closure and bulk autophagic flux. The UEVL mutation (Δ43-139) impairs autophagosome closure without disrupting ESCRT-I complex assembly or endosomal function. Loss of UEVL function leads to active TBK1 accumulation on phagophores (detected by LC3 proximity proteomics), resulting in increased p62 phosphorylation and inclusion body formation.\",\n      \"method\": \"Knock-in mouse model with UEVL deletion, LC3 proximity proteomics (BioID), autophagic flux assays, p62/ubiquitin accumulation analysis, TBK1 activity measurements\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — in vivo knock-in mutagenesis, proximity proteomics, multiple orthogonal readouts separating ESCRT-I vs. autophagy functions\",\n      \"pmids\": [\"39607828\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"VPS37A directs TNFR1 to lysosomal degradation via the autophagy-lysosomal pathway, thereby suppressing NF-κB nuclear translocation and transcriptional activity under metabolic stress in colorectal cancer cells.\",\n      \"method\": \"VPS37A overexpression, RNA sequencing, NF-κB luciferase reporter assay, lysosomal inhibition experiments, xenograft assays\",\n      \"journal\": \"Oncology research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple functional assays and reporter assays, single lab study\",\n      \"pmids\": [\"40746890\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"HCRP-1/VPS37A depletion induces Src and FAK phosphorylation in prostate cancer cells, promoting cell migration, invasion, and angiogenesis; these effects are reversed by Src inhibitor PP2 or FAK inhibitor, placing VPS37A upstream of Src/FAK signaling. Note: the original research paper (PMID 31929761) was subsequently retracted (PMID 34803514).\",\n      \"method\": \"Co-immunoprecipitation, western blot, transwell/tube formation assays, pharmacological inhibition with PP2 and FAK inhibitor — RETRACTED\",\n      \"journal\": \"International journal of biological sciences\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — single Co-IP/western blot; paper retracted\",\n      \"pmids\": [\"31929761\", \"34803514\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"In MLKL-deficient colorectal cancer cells, autophagy becomes critically dependent on VPS37A, and p38 MAPK activation prevents VPS37A from supporting autophagy, triggering parthanatos cell death.\",\n      \"method\": \"MLKL gene knockout, VPS37A functional dependency assay, p38 MAPK inhibition/activation, cell death assays\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — genetic epistasis in cell lines, preprint, single lab\",\n      \"pmids\": [],\n      \"is_preprint\": true\n    }\n  ],\n  \"current_model\": \"VPS37A is a subunit of the mammalian ESCRT-I complex that uses its mod(r) domain to interact with Tsg101 and hVps28 and localizes to late endosomes to drive lysosomal degradation of ubiquitinated membrane receptors (e.g., EGFR, TNFR1, glucagon receptor); additionally, its N-terminal ubiquitin E2 variant-like (UEVL) domain directs VPS37A to the phagophore independently of ESCRT-I assembly, where it recruits VPS28 and CHMP2A to coordinate ESCRT-III–VPS4-dependent phagophore closure during autophagy, with loss of UEVL function causing TBK1 accumulation on unclosed phagophores and enhanced p62 phosphorylation and inclusion formation.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"VPS37A is a core subunit of the mammalian ESCRT-I complex that functions in both endosomal sorting and autophagosome biogenesis. Through its mod(r) domain, VPS37A assembles with Tsg101 and VPS28 on late endosomes to drive lysosomal degradation of ubiquitinated membrane receptors including EGFR, TNFR1, and the glucagon receptor, with hepatocyte-specific loss causing endosomal accumulation of the glucagon receptor and overactivation of cAMP/PKA/CREB-dependent gluconeogenesis [PMID:15240819, PMID:36243006, PMID:40746890]. Independently of its ESCRT-I assembly function, VPS37A uses its N-terminal ubiquitin E2 variant-like (UEVL) domain to localize to the phagophore, where it recruits VPS28 and the ESCRT-III subunit CHMP2A to mediate VPS4-dependent phagophore closure; loss of UEVL function blocks autophagosome completion, causes TBK1 accumulation on unclosed phagophores, and drives p62 hyperphosphorylation and inclusion body formation [PMID:31519728, PMID:39607828].\",\n  \"teleology\": [\n    {\n      \"year\": 2004,\n      \"claim\": \"Identification of VPS37A as a bona fide ESCRT-I subunit resolved how a then-uncharacterized protein (HCRP1) links the upstream Hrs/STAM machinery to the Tsg101–VPS28 core complex and established its requirement for lysosomal degradation of EGF receptors.\",\n      \"evidence\": \"Reciprocal co-IP, size-exclusion co-fractionation, colocalization on LAMP1-positive endosomes, and siRNA knockdown showing impaired EGFR degradation in human cells\",\n      \"pmids\": [\"15240819\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Structural basis of the mod(r)-mediated interaction with Tsg101 not resolved\",\n        \"Whether VPS37A has functions beyond the MVB pathway was unknown\",\n        \"No information on receptor specificity beyond EGFR\"\n      ]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"A genome-wide CRISPR screen revealed that VPS37A's role extends beyond endosomal sorting to phagophore closure during autophagy, and domain dissection showed that the N-terminal UEV domain is required for phagophore localization and ESCRT-III recruitment but dispensable for ESCRT-I complex formation.\",\n      \"evidence\": \"FACS-based HaloTag-LC3 autophagosome completion screen, UEV deletion mutants, epistasis with CHMP2A and VPS4, live imaging in human cells\",\n      \"pmids\": [\"31519728\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Identity of the phagophore receptor or lipid determinant recognized by the UEV domain unknown\",\n        \"Downstream signaling consequences of failed phagophore closure not addressed\"\n      ]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Extending VPS37A's endosomal function to metabolic physiology, hepatocyte-specific knockdown demonstrated that VPS37A controls the spatiotemporal localization of the glucagon receptor, uncoupling gluconeogenesis from β-oxidation in vivo.\",\n      \"evidence\": \"Cy5-glucagon trafficking, hepatocyte-specific siRNA in mice, cAMP/PKA/p-CREB signaling readouts, receptor re-localization rescue\",\n      \"pmids\": [\"36243006\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Whether VPS37A similarly regulates other hepatocyte GPCRs is untested\",\n        \"Mechanism by which glucagon receptor is preferentially retained in endosomes upon VPS37A loss not defined\"\n      ]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"An in vivo knock-in model pinpointed the UEVL domain (β-strands 43–139) as the autophagy-specific module of VPS37A and revealed that failed phagophore closure leads to TBK1 accumulation on open phagophores, enhanced p62 phosphorylation, and inclusion body formation—linking ESCRT-mediated membrane sealing to innate immune kinase signaling.\",\n      \"evidence\": \"UEVL-deletion knock-in mice, LC3 BioID proximity proteomics, autophagic flux and p62/ubiquitin accumulation assays, TBK1 activity measurements\",\n      \"pmids\": [\"39607828\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"How TBK1 is activated by open phagophores is mechanistically unclear\",\n        \"Whether the inclusion body phenotype leads to neurodegeneration or tissue pathology in vivo not established\",\n        \"No structural model of UEVL domain at atomic resolution\"\n      ]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"VPS37A was shown to direct TNFR1 to lysosomal degradation via the autophagy-lysosomal pathway, suppressing NF-κB signaling in colorectal cancer cells under metabolic stress, broadening the receptor repertoire controlled by VPS37A.\",\n      \"evidence\": \"VPS37A overexpression, RNA-seq, NF-κB luciferase reporter, lysosomal inhibition, xenograft assays\",\n      \"pmids\": [\"40746890\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Whether TNFR1 degradation uses the MVB or autophagy arm of VPS37A function not distinguished\",\n        \"Single-lab study; awaits independent confirmation\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The phagophore-targeting mechanism of the UEVL domain remains unresolved: neither the membrane determinant (lipid species or protein receptor) recognized by the UEVL domain nor the structural basis for selective phagophore versus endosome engagement has been identified.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"No binding partner or lipid ligand identified for the UEVL domain on the phagophore\",\n        \"No high-resolution structure of VPS37A UEVL domain available\",\n        \"In vivo physiological consequences of UEVL loss (beyond TBK1/p62) in disease models not characterized\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [0, 1, 3]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005768\", \"supporting_discovery_ids\": [0, 2]},\n      {\"term_id\": \"GO:0031410\", \"supporting_discovery_ids\": [0, 1, 3]},\n      {\"term_id\": \"GO:0005764\", \"supporting_discovery_ids\": [0, 2, 4]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-5653656\", \"supporting_discovery_ids\": [0, 2]},\n      {\"term_id\": \"R-HSA-9612973\", \"supporting_discovery_ids\": [1, 3, 4]}\n    ],\n    \"complexes\": [\n      \"ESCRT-I\"\n    ],\n    \"partners\": [\n      \"TSG101\",\n      \"VPS28\",\n      \"HGS\",\n      \"CHMP2A\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}