{"gene":"CHMP2A","run_date":"2026-06-09T22:57:18","timeline":{"discoveries":[{"year":2023,"finding":"Cryo-EM structures of membrane-coated CHMP2A-CHMP3 filaments (3.3 and 3.6 Å resolution) reveal helical filaments assembled by CHMP2A-CHMP3 heterodimers in the open ESCRT-III conformation, generating a partially positive-charged membrane interaction surface, positioning N-terminal motifs for membrane interaction and C-terminal VPS4 target sequences toward the tube interior; inter-filament interactions are electrostatic, facilitating filament sliding upon VPS4-mediated remodeling. VPS4 can constrict and cleave CHMP2A-CHMP3 membrane tubes, establishing CHMP2A-CHMP3-VPS4 as a minimal membrane fission machinery.","method":"Cryo-EM structure determination, fluorescence microscopy, high-speed atomic force microscopy","journal":"Nature structural & molecular biology","confidence":"High","confidence_rationale":"Tier 1 / Strong — atomic-resolution cryo-EM structures with functional validation by AFM and fluorescence microscopy in a single rigorous study","pmids":["36604498"],"is_preprint":false},{"year":2021,"finding":"CHMP2A does not display lipid specificity and requires CHMP3 for binding significantly to membranes, in contrast to CHMP2B which binds independently and is enhanced by PI(4,5)P2. CHMP2A (+CHMP3) binds homogeneously on membranes but has no significant effect on membrane rigidity, whereas CHMP2B strongly rigidifies membranes.","method":"In vitro binding assays with purified proteins on biomimetic membranes, membrane mechanics measurements","journal":"BMC biology","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro reconstitution with purified proteins, multiple orthogonal biophysical methods, single lab","pmids":["33832485"],"is_preprint":false},{"year":2004,"finding":"Mammalian CHMP2A (mVps2) interacts with the AAA-ATPase SKD1/VPS4B and localizes to an aberrant endosomal compartment induced by ATPase-deficient SKD1(E235Q). The N-terminal coiled-coil region of mVps2 is required for formation of the E235Q compartment but not for binding to SKD1.","method":"Yeast two-hybrid screening, co-immunoprecipitation, immunofluorescence localization with SKD1(E235Q) dominant-negative","journal":"Journal of cell science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — yeast two-hybrid plus co-IP plus localization, single lab, multiple orthogonal methods","pmids":["15173323"],"is_preprint":false},{"year":2021,"finding":"In yeast, the ESCRT-III subunit Vps2 (ortholog of CHMP2A) requires three minimal features for function: spiral formation, lateral association of spirals through heteropolymerization, and binding to the AAA+ ATPase Vps4. Mutations in the helix-1 region of Vps2 can functionally replace Vps24 in S. cerevisiae, demonstrating functional interchangeability through shared structural features.","method":"Mutagenesis, genetic complementation, engineering and genetic selection in S. cerevisiae","journal":"eLife","confidence":"Medium","confidence_rationale":"Tier 1 / Moderate — mutagenesis and genetic epistasis in yeast ortholog, single lab, multiple engineered variants tested","pmids":["34028356"],"is_preprint":false},{"year":2020,"finding":"Conditional depletion of CHMP2A (an ESCRT-III component required for phagophore/autophagosome closure) stabilizes intracellular death-inducing signaling complexes (iDISCs) on immature autophagosomal membranes and induces Caspase-8-dependent apoptosis. This Caspase-8 activation is blocked by ATG7 deletion, placing CHMP2A upstream of autophagosome-based iDISC assembly.","method":"Conditional knockdown/knockout, genetic epistasis (ATG7 deletion), Caspase-8 activity assays, in vivo xenograft model","journal":"Cell death and differentiation","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — clean conditional KD/KO with defined cellular and molecular phenotype, genetic epistasis, in vivo validation, single lab","pmids":["32807832"],"is_preprint":false},{"year":2022,"finding":"Deletion of CHMP2A activates NF-κB in tumor cells to mediate increased chemokine secretion promoting NK cell migration. In HNSCC cells, CHMP2A mediates tumor resistance to NK cells via secretion of extracellular vesicles (EVs) expressing MICA/B and TRAIL, which induce apoptosis of NK cells to inhibit their antitumor activity.","method":"CRISPR-Cas9 whole-genome screen, CHMP2A knockout, NF-κB pathway analysis, EV characterization, NK cell killing assays, xenograft mouse model","journal":"Nature communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — CRISPR KO with mechanistic pathway analysis, multiple assays, in vivo validation, single lab","pmids":["35393416"],"is_preprint":false},{"year":2025,"finding":"CHMP2A knockout causes significant delay (but not failure) in cytokinetic abscission, accompanied by progressive organization defects in CHMP4B, CHMP3, and CHMP1B at the abscission site while IST1 and CHMP2B are minimally disrupted. This demonstrates that CHMP2A acts as a hierarchical organizer of ESCRT-III subunit assembly during abscission, with downstream subunits (CHMP4B, CHMP3, CHMP1B) depending on CHMP2A for correct localization.","method":"Live cell imaging, structured illumination microscopy (SIM), correlative light-electron microscopy, CHMP2A knockout","journal":"Molecular biology of the cell","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — clean KO with defined phenotype, multiple high-resolution imaging modalities, single lab","pmids":["40928930"],"is_preprint":false},{"year":2024,"finding":"CHMP2A KO in immunocompetent mouse head and neck squamous cell carcinoma model leads to increased CD4+ T cells, CD8+ T cells, and NK cells, and fewer myeloid-derived suppressor cells (MDSCs) in the tumor microenvironment, demonstrating that CHMP2A regulates broad immune cell-mediated antitumor activity beyond NK cells alone. No difference in tumor development was observed in immunodeficient mice, confirming the effect is immune-mediated.","method":"CRISPR/Cas9 knockout, orthotopic transplantation in syngeneic immunocompetent and immunodeficient mice, immune cell profiling","journal":"Journal for immunotherapy of cancer","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — clean KO with in vivo immune profiling, immunodeficient control experiment, single lab","pmids":["38702144"],"is_preprint":false},{"year":2021,"finding":"PTEN overexpression upregulates CHMP2A, and the beneficial effect of PTEN on autophagy flux and cell protection after ischemia/reperfusion injury is abolished when CHMP2A is silenced, placing CHMP2A downstream of PTEN in a pathway regulating phagosome closure and autolysosome formation.","method":"PTEN transgenic mouse model, mass spectrometry proteomics, CHMP2A siRNA knockdown, autophagy flux assays","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic epistasis via rescue experiment (CHMP2A knockdown abolishes PTEN benefit), multiple methods, single lab","pmids":["34789720"],"is_preprint":false},{"year":2024,"finding":"CHMP2A associates with specific lipid species in dividing HeLa cells as detected by lipid-trap mass spectrometry (immunoprecipitation of GFP-CHMP2A followed by lipidomics), identifying lipid-protein interactions during cytokinesis.","method":"Lipid-trap mass spectrometry (GFP immunoprecipitation coupled to lipidomic analysis) in dividing HeLa cells","journal":"bioRxiv","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single method, preprint, no functional validation of specific lipid interactions","pmids":["bio_10.1101_2024.12.13.627510"],"is_preprint":true}],"current_model":"CHMP2A is a core ESCRT-III subunit that forms heterodimeric filaments with CHMP3 in the open conformation to coat and constrict membrane tubes, requires CHMP3 for membrane binding (lacking intrinsic lipid specificity), interacts with the AAA-ATPase VPS4/SKD1 via its C-terminal region to drive membrane fission, acts as a hierarchical organizer of ESCRT-III subunit assembly during cytokinetic abscission, mediates autophagosome/phagophore closure to regulate iDISC-dependent Caspase-8 apoptosis, and controls tumor immune evasion by regulating NF-κB-driven chemokine secretion and extracellular vesicle-mediated NK cell apoptosis."},"narrative":{"mechanistic_narrative":"CHMP2A is a core ESCRT-III subunit that drives membrane remodeling and fission as part of the minimal CHMP2A-CHMP3-VPS4 machinery [PMID:36604498]. Cryo-EM of membrane-coated filaments shows that CHMP2A and CHMP3 assemble as heterodimers in the open ESCRT-III conformation into helical filaments whose partially positive surface engages the membrane, with N-terminal motifs positioned for membrane interaction and C-terminal VPS4 target sequences facing the tube interior; electrostatic inter-filament contacts permit VPS4-driven sliding, constriction, and tube cleavage [PMID:36604498]. CHMP2A itself lacks intrinsic lipid specificity and depends on CHMP3 to bind membranes, and it does not appreciably alter membrane rigidity, distinguishing it from CHMP2B [PMID:33832485]. Engagement of the AAA-ATPase VPS4/SKD1 occurs independently of the N-terminal coiled-coil, which is instead required for assembly into ESCRT-III membrane structures [PMID:15173323], and yeast ortholog analysis confirms that spiral formation, lateral heteropolymerization, and VPS4 binding are the minimal functional features of this subunit [PMID:34028356]. During cytokinetic abscission CHMP2A acts as a hierarchical organizer of ESCRT-III assembly, with CHMP4B, CHMP3, and CHMP1B depending on it for correct localization [PMID:40928930]. Beyond cytokinesis, CHMP2A mediates phagophore/autophagosome closure: its depletion stabilizes intracellular death-inducing signaling complexes on immature autophagosomal membranes and triggers ATG7-dependent Caspase-8 apoptosis [PMID:32807832], and it functions downstream of PTEN to support autophagy flux and protection after ischemia/reperfusion injury [PMID:34789720]. In tumor cells CHMP2A restrains antitumor immunity by suppressing NF-κB-driven chemokine secretion and by promoting extracellular-vesicle-mediated NK cell apoptosis, with its loss broadly enhancing immune-cell-mediated tumor control [PMID:35393416, PMID:38702144].","teleology":[{"year":2004,"claim":"Established that mammalian CHMP2A physically engages the VPS4-family ATPase and depends on its N-terminal coiled-coil for assembly onto endosomal membranes, separating its ATPase-binding function from its membrane-targeting function.","evidence":"Yeast two-hybrid, co-IP, and immunofluorescence with the dominant-negative SKD1(E235Q) in mammalian cells","pmids":["15173323"],"confidence":"Medium","gaps":["Did not resolve the structural basis of the CHMP2A-VPS4 interaction","No direct demonstration of membrane fission"]},{"year":2020,"claim":"Placed CHMP2A in autophagosome closure by showing its loss stabilizes death-inducing complexes on immature membranes and triggers Caspase-8 apoptosis, linking ESCRT-III membrane closure to cell-death control.","evidence":"Conditional knockdown/knockout, ATG7-deletion epistasis, Caspase-8 assays, xenograft model","pmids":["32807832"],"confidence":"Medium","gaps":["Molecular composition and membrane attachment of iDISCs not fully resolved","Mechanism of phagophore sealing by CHMP2A not directly visualized"]},{"year":2021,"claim":"Demonstrated that CHMP2A lacks intrinsic lipid specificity and requires CHMP3 for membrane binding, defining its biophysical role relative to the membrane-rigidifying CHMP2B paralog.","evidence":"In vitro reconstitution with purified proteins on biomimetic membranes and membrane mechanics measurements","pmids":["33832485"],"confidence":"High","gaps":["Did not establish the filament architecture underlying binding","Physiological membrane substrate composition not addressed"]},{"year":2021,"claim":"Reduced the subunit to three minimal functional requirements—spiral formation, lateral heteropolymerization, and VPS4 binding—using the yeast ortholog, defining the conserved logic of ESCRT-III function.","evidence":"Mutagenesis, genetic complementation, and engineered selection in S. cerevisiae Vps2","pmids":["34028356"],"confidence":"Medium","gaps":["Inferred from yeast ortholog rather than human CHMP2A","Did not test membrane fission directly"]},{"year":2021,"claim":"Positioned CHMP2A downstream of PTEN in autophagy regulation, showing CHMP2A is required for PTEN-mediated autophagy flux and tissue protection after ischemia/reperfusion.","evidence":"PTEN transgenic mice, proteomics, CHMP2A siRNA rescue, autophagy flux assays","pmids":["34789720"],"confidence":"Medium","gaps":["Mechanism by which PTEN upregulates CHMP2A unclear","Direct role of CHMP2A in autolysosome formation not visualized"]},{"year":2022,"claim":"Identified CHMP2A as a tumor immune-evasion factor that suppresses NF-κB-driven chemokine secretion and drives NK-cell-killing via MICA/B- and TRAIL-bearing extracellular vesicles.","evidence":"Genome-wide CRISPR screen, CHMP2A KO, NF-κB analysis, EV characterization, NK killing assays, xenografts","pmids":["35393416"],"confidence":"Medium","gaps":["How ESCRT-III membrane activity connects mechanistically to NF-κB is unresolved","EV cargo loading mechanism not defined"]},{"year":2023,"claim":"Provided the atomic structural mechanism: CHMP2A-CHMP3 open-conformation heterodimers form helical membrane-coating filaments cleaved by VPS4, establishing CHMP2A-CHMP3-VPS4 as a minimal fission machine.","evidence":"Cryo-EM at 3.3/3.6 Å, high-speed AFM, fluorescence microscopy","pmids":["36604498"],"confidence":"High","gaps":["In-cell relevance of the reconstituted geometry not tested","Stoichiometry with other ESCRT-III subunits in physiological filaments unresolved"]},{"year":2024,"claim":"Extended the immune-evasion role in vivo, showing CHMP2A loss broadens antitumor immunity (more T and NK cells, fewer MDSCs) and confirmed the effect is immune-dependent.","evidence":"CRISPR KO, syngeneic immunocompetent vs immunodeficient orthotopic transplantation, immune profiling","pmids":["38702144"],"confidence":"Medium","gaps":["Cell-intrinsic mechanism altering MDSC and T-cell recruitment not defined","Whether effect is EV-dependent in vivo not isolated"]},{"year":2024,"claim":"Began mapping CHMP2A lipid environment during division by capturing associated lipid species in dividing cells.","evidence":"Lipid-trap mass spectrometry (GFP-CHMP2A IP plus lipidomics) in dividing HeLa cells (preprint)","pmids":["bio_10.1101_2024.12.13.627510"],"confidence":"Low","gaps":["Single method, preprint, no functional validation of specific lipid interactions","Direct binding vs co-purification not distinguished"]},{"year":2025,"claim":"Defined CHMP2A as a hierarchical organizer of abscission, with downstream ESCRT-III subunits depending on it for correct localization while abscission is delayed rather than abolished.","evidence":"Live imaging, SIM, correlative light-electron microscopy in CHMP2A KO cells","pmids":["40928930"],"confidence":"Medium","gaps":["Redundancy compensating for CHMP2A loss not identified","Order of subunit recruitment relative to VPS4 not fully resolved"]},{"year":null,"claim":"How CHMP2A's membrane-fission activity is mechanistically coupled to its signaling roles (NF-κB modulation, EV-mediated immune suppression, PTEN-dependent autophagy) remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No direct link established between filament/fission activity and NF-κB control","Mechanism of immune-relevant EV biogenesis by CHMP2A undefined"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0005198","term_label":"structural molecule activity","supporting_discovery_ids":[0,1,6]},{"term_id":"GO:0008289","term_label":"lipid binding","supporting_discovery_ids":[1]}],"localization":[{"term_id":"GO:0005768","term_label":"endosome","supporting_discovery_ids":[2]},{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[0,1]}],"pathway":[{"term_id":"R-HSA-1640170","term_label":"Cell Cycle","supporting_discovery_ids":[6]},{"term_id":"R-HSA-9612973","term_label":"Autophagy","supporting_discovery_ids":[4,8]},{"term_id":"R-HSA-5653656","term_label":"Vesicle-mediated transport","supporting_discovery_ids":[0]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[5,7]}],"complexes":["ESCRT-III"],"partners":["CHMP3","VPS4B","CHMP4B","CHMP1B"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"O43633","full_name":"Charged multivesicular body protein 2a","aliases":["Chromatin-modifying protein 2a","CHMP2a","Putative breast adenocarcinoma marker BC-2","Vacuolar protein sorting-associated protein 2-1","Vps2-1","hVps2-1"],"length_aa":222,"mass_kda":25.1,"function":"Probable core component of the endosomal sorting required for transport complex III (ESCRT-III) which is involved in multivesicular bodies (MVBs) formation and sorting of endosomal cargo proteins into MVBs. MVBs contain intraluminal vesicles (ILVs) that are generated by invagination and scission from the limiting membrane of the endosome and mostly are delivered to lysosomes enabling degradation of membrane proteins, such as stimulated growth factor receptors, lysosomal enzymes and lipids. The MVB pathway appears to require the sequential function of ESCRT-O, -I,-II and -III complexes. ESCRT-III proteins mostly dissociate from the invaginating membrane before the ILV is released. The ESCRT machinery also functions in topologically equivalent membrane fission events, such as the terminal stages of cytokinesis (PubMed:21310966). Together with SPAST, the ESCRT-III complex promotes nuclear envelope sealing and mitotic spindle disassembly during late anaphase (PubMed:26040712). Recruited to the reforming nuclear envelope (NE) during anaphase by LEMD2 (PubMed:28242692). ESCRT-III proteins are believed to mediate the necessary vesicle extrusion and/or membrane fission activities, possibly in conjunction with the AAA ATPase VPS4 (Microbial infection) The ESCRT machinery functions in topologically equivalent membrane fission events, such as the budding of enveloped viruses (HIV-1 and other lentiviruses). Involved in HIV-1 p6- and p9-dependent virus release","subcellular_location":"Late endosome membrane; Nucleus envelope","url":"https://www.uniprot.org/uniprotkb/O43633/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":true,"resolved_as":"","url":"https://depmap.org/portal/gene/CHMP2A","classification":"Common Essential","n_dependent_lines":1207,"n_total_lines":1208,"dependency_fraction":0.9991721854304636},"opencell":{"profiled":true,"resolved_as":"","ensg_id":"ENSG00000130724","cell_line_id":"CID000773","localizations":[{"compartment":"cytoplasmic","grade":3},{"compartment":"nucleoplasm","grade":3},{"compartment":"vesicles","grade":1}],"interactors":[{"gene":"MYO1B","stoichiometry":0.2},{"gene":"TXNL4A","stoichiometry":0.2},{"gene":"CLTA","stoichiometry":0.2},{"gene":"CLTB","stoichiometry":0.2},{"gene":"VPS4A","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/target/CID000773","total_profiled":1310},"omim":[{"mim_id":"610902","title":"VESSICLE TRAFFICKING 1; VTA1","url":"https://www.omim.org/entry/610902"},{"mim_id":"610897","title":"CHARGED MULTIVESICULAR BODY PROTEIN 4B; CHMP4B","url":"https://www.omim.org/entry/610897"},{"mim_id":"610893","title":"CHARGED MULTIVESICULAR BODY PROTEIN 2A; CHMP2A","url":"https://www.omim.org/entry/610893"},{"mim_id":"610052","title":"CHARGED MULTIVESICULAR BODY PROTEIN 3; CHMP3","url":"https://www.omim.org/entry/610052"},{"mim_id":"609983","title":"VACUOLAR PROTEIN SORTING 4 HOMOLOG B; VPS4B","url":"https://www.omim.org/entry/609983"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Cytosol","reliability":"Approved"},{"location":"Nucleoplasm","reliability":"Additional"},{"location":"Plasma membrane","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/CHMP2A"},"hgnc":{"alias_symbol":["BC-2","CHMP2","VPS2","VPS2A"],"prev_symbol":[]},"alphafold":{"accession":"O43633","domains":[{"cath_id":"-","chopping":"8-143_163-173","consensus_level":"medium","plddt":86.5434,"start":8,"end":173}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/O43633","model_url":"https://alphafold.ebi.ac.uk/files/AF-O43633-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-O43633-F1-predicted_aligned_error_v6.png","plddt_mean":75.19},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=CHMP2A","jax_strain_url":"https://www.jax.org/strain/search?query=CHMP2A"},"sequence":{"accession":"O43633","fasta_url":"https://rest.uniprot.org/uniprotkb/O43633.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/O43633/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/O43633"}},"corpus_meta":[{"pmid":"7670109","id":"PMC_7670109","title":"In vitro 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spectrometry","date":"2024-12-15","source":"bioRxiv","url":"https://doi.org/10.1101/2024.12.13.627510","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2024.11.19.624330","title":"The ALS- and FTD-associated proteins Annexin A11 and CHMP2B act sequentially in membrane repair","date":"2024-11-21","source":"bioRxiv","url":"https://doi.org/10.1101/2024.11.19.624330","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":14673,"output_tokens":2703,"usd":0.042282,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":9951,"output_tokens":3659,"usd":0.070615,"stage2_stop_reason":"end_turn"},"total_usd":0.112897,"stage1_batch_id":"msgbatch_01ACAxJQabDsht39JXeWG22d","stage2_batch_id":"msgbatch_01QEU22A9U5sbPTgsMzTmvSf","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2023,\n      \"finding\": \"Cryo-EM structures of membrane-coated CHMP2A-CHMP3 filaments (3.3 and 3.6 Å resolution) reveal helical filaments assembled by CHMP2A-CHMP3 heterodimers in the open ESCRT-III conformation, generating a partially positive-charged membrane interaction surface, positioning N-terminal motifs for membrane interaction and C-terminal VPS4 target sequences toward the tube interior; inter-filament interactions are electrostatic, facilitating filament sliding upon VPS4-mediated remodeling. VPS4 can constrict and cleave CHMP2A-CHMP3 membrane tubes, establishing CHMP2A-CHMP3-VPS4 as a minimal membrane fission machinery.\",\n      \"method\": \"Cryo-EM structure determination, fluorescence microscopy, high-speed atomic force microscopy\",\n      \"journal\": \"Nature structural & molecular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — atomic-resolution cryo-EM structures with functional validation by AFM and fluorescence microscopy in a single rigorous study\",\n      \"pmids\": [\"36604498\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"CHMP2A does not display lipid specificity and requires CHMP3 for binding significantly to membranes, in contrast to CHMP2B which binds independently and is enhanced by PI(4,5)P2. CHMP2A (+CHMP3) binds homogeneously on membranes but has no significant effect on membrane rigidity, whereas CHMP2B strongly rigidifies membranes.\",\n      \"method\": \"In vitro binding assays with purified proteins on biomimetic membranes, membrane mechanics measurements\",\n      \"journal\": \"BMC biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro reconstitution with purified proteins, multiple orthogonal biophysical methods, single lab\",\n      \"pmids\": [\"33832485\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"Mammalian CHMP2A (mVps2) interacts with the AAA-ATPase SKD1/VPS4B and localizes to an aberrant endosomal compartment induced by ATPase-deficient SKD1(E235Q). The N-terminal coiled-coil region of mVps2 is required for formation of the E235Q compartment but not for binding to SKD1.\",\n      \"method\": \"Yeast two-hybrid screening, co-immunoprecipitation, immunofluorescence localization with SKD1(E235Q) dominant-negative\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — yeast two-hybrid plus co-IP plus localization, single lab, multiple orthogonal methods\",\n      \"pmids\": [\"15173323\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"In yeast, the ESCRT-III subunit Vps2 (ortholog of CHMP2A) requires three minimal features for function: spiral formation, lateral association of spirals through heteropolymerization, and binding to the AAA+ ATPase Vps4. Mutations in the helix-1 region of Vps2 can functionally replace Vps24 in S. cerevisiae, demonstrating functional interchangeability through shared structural features.\",\n      \"method\": \"Mutagenesis, genetic complementation, engineering and genetic selection in S. cerevisiae\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — mutagenesis and genetic epistasis in yeast ortholog, single lab, multiple engineered variants tested\",\n      \"pmids\": [\"34028356\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Conditional depletion of CHMP2A (an ESCRT-III component required for phagophore/autophagosome closure) stabilizes intracellular death-inducing signaling complexes (iDISCs) on immature autophagosomal membranes and induces Caspase-8-dependent apoptosis. This Caspase-8 activation is blocked by ATG7 deletion, placing CHMP2A upstream of autophagosome-based iDISC assembly.\",\n      \"method\": \"Conditional knockdown/knockout, genetic epistasis (ATG7 deletion), Caspase-8 activity assays, in vivo xenograft model\",\n      \"journal\": \"Cell death and differentiation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean conditional KD/KO with defined cellular and molecular phenotype, genetic epistasis, in vivo validation, single lab\",\n      \"pmids\": [\"32807832\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Deletion of CHMP2A activates NF-κB in tumor cells to mediate increased chemokine secretion promoting NK cell migration. In HNSCC cells, CHMP2A mediates tumor resistance to NK cells via secretion of extracellular vesicles (EVs) expressing MICA/B and TRAIL, which induce apoptosis of NK cells to inhibit their antitumor activity.\",\n      \"method\": \"CRISPR-Cas9 whole-genome screen, CHMP2A knockout, NF-κB pathway analysis, EV characterization, NK cell killing assays, xenograft mouse model\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — CRISPR KO with mechanistic pathway analysis, multiple assays, in vivo validation, single lab\",\n      \"pmids\": [\"35393416\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"CHMP2A knockout causes significant delay (but not failure) in cytokinetic abscission, accompanied by progressive organization defects in CHMP4B, CHMP3, and CHMP1B at the abscission site while IST1 and CHMP2B are minimally disrupted. This demonstrates that CHMP2A acts as a hierarchical organizer of ESCRT-III subunit assembly during abscission, with downstream subunits (CHMP4B, CHMP3, CHMP1B) depending on CHMP2A for correct localization.\",\n      \"method\": \"Live cell imaging, structured illumination microscopy (SIM), correlative light-electron microscopy, CHMP2A knockout\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean KO with defined phenotype, multiple high-resolution imaging modalities, single lab\",\n      \"pmids\": [\"40928930\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"CHMP2A KO in immunocompetent mouse head and neck squamous cell carcinoma model leads to increased CD4+ T cells, CD8+ T cells, and NK cells, and fewer myeloid-derived suppressor cells (MDSCs) in the tumor microenvironment, demonstrating that CHMP2A regulates broad immune cell-mediated antitumor activity beyond NK cells alone. No difference in tumor development was observed in immunodeficient mice, confirming the effect is immune-mediated.\",\n      \"method\": \"CRISPR/Cas9 knockout, orthotopic transplantation in syngeneic immunocompetent and immunodeficient mice, immune cell profiling\",\n      \"journal\": \"Journal for immunotherapy of cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean KO with in vivo immune profiling, immunodeficient control experiment, single lab\",\n      \"pmids\": [\"38702144\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"PTEN overexpression upregulates CHMP2A, and the beneficial effect of PTEN on autophagy flux and cell protection after ischemia/reperfusion injury is abolished when CHMP2A is silenced, placing CHMP2A downstream of PTEN in a pathway regulating phagosome closure and autolysosome formation.\",\n      \"method\": \"PTEN transgenic mouse model, mass spectrometry proteomics, CHMP2A siRNA knockdown, autophagy flux assays\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic epistasis via rescue experiment (CHMP2A knockdown abolishes PTEN benefit), multiple methods, single lab\",\n      \"pmids\": [\"34789720\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"CHMP2A associates with specific lipid species in dividing HeLa cells as detected by lipid-trap mass spectrometry (immunoprecipitation of GFP-CHMP2A followed by lipidomics), identifying lipid-protein interactions during cytokinesis.\",\n      \"method\": \"Lipid-trap mass spectrometry (GFP immunoprecipitation coupled to lipidomic analysis) in dividing HeLa cells\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single method, preprint, no functional validation of specific lipid interactions\",\n      \"pmids\": [\"bio_10.1101_2024.12.13.627510\"],\n      \"is_preprint\": true\n    }\n  ],\n  \"current_model\": \"CHMP2A is a core ESCRT-III subunit that forms heterodimeric filaments with CHMP3 in the open conformation to coat and constrict membrane tubes, requires CHMP3 for membrane binding (lacking intrinsic lipid specificity), interacts with the AAA-ATPase VPS4/SKD1 via its C-terminal region to drive membrane fission, acts as a hierarchical organizer of ESCRT-III subunit assembly during cytokinetic abscission, mediates autophagosome/phagophore closure to regulate iDISC-dependent Caspase-8 apoptosis, and controls tumor immune evasion by regulating NF-κB-driven chemokine secretion and extracellular vesicle-mediated NK cell apoptosis.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"CHMP2A is a core ESCRT-III subunit that drives membrane remodeling and fission as part of the minimal CHMP2A-CHMP3-VPS4 machinery [#0]. Cryo-EM of membrane-coated filaments shows that CHMP2A and CHMP3 assemble as heterodimers in the open ESCRT-III conformation into helical filaments whose partially positive surface engages the membrane, with N-terminal motifs positioned for membrane interaction and C-terminal VPS4 target sequences facing the tube interior; electrostatic inter-filament contacts permit VPS4-driven sliding, constriction, and tube cleavage [#0]. CHMP2A itself lacks intrinsic lipid specificity and depends on CHMP3 to bind membranes, and it does not appreciably alter membrane rigidity, distinguishing it from CHMP2B [#1]. Engagement of the AAA-ATPase VPS4/SKD1 occurs independently of the N-terminal coiled-coil, which is instead required for assembly into ESCRT-III membrane structures [#2], and yeast ortholog analysis confirms that spiral formation, lateral heteropolymerization, and VPS4 binding are the minimal functional features of this subunit [#3]. During cytokinetic abscission CHMP2A acts as a hierarchical organizer of ESCRT-III assembly, with CHMP4B, CHMP3, and CHMP1B depending on it for correct localization [#6]. Beyond cytokinesis, CHMP2A mediates phagophore/autophagosome closure: its depletion stabilizes intracellular death-inducing signaling complexes on immature autophagosomal membranes and triggers ATG7-dependent Caspase-8 apoptosis [#4], and it functions downstream of PTEN to support autophagy flux and protection after ischemia/reperfusion injury [#8]. In tumor cells CHMP2A restrains antitumor immunity by suppressing NF-\\u03baB-driven chemokine secretion and by promoting extracellular-vesicle-mediated NK cell apoptosis, with its loss broadly enhancing immune-cell-mediated tumor control [#5, #7].\",\n  \"teleology\": [\n    {\n      \"year\": 2004,\n      \"claim\": \"Established that mammalian CHMP2A physically engages the VPS4-family ATPase and depends on its N-terminal coiled-coil for assembly onto endosomal membranes, separating its ATPase-binding function from its membrane-targeting function.\",\n      \"evidence\": \"Yeast two-hybrid, co-IP, and immunofluorescence with the dominant-negative SKD1(E235Q) in mammalian cells\",\n      \"pmids\": [\"15173323\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Did not resolve the structural basis of the CHMP2A-VPS4 interaction\", \"No direct demonstration of membrane fission\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Placed CHMP2A in autophagosome closure by showing its loss stabilizes death-inducing complexes on immature membranes and triggers Caspase-8 apoptosis, linking ESCRT-III membrane closure to cell-death control.\",\n      \"evidence\": \"Conditional knockdown/knockout, ATG7-deletion epistasis, Caspase-8 assays, xenograft model\",\n      \"pmids\": [\"32807832\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular composition and membrane attachment of iDISCs not fully resolved\", \"Mechanism of phagophore sealing by CHMP2A not directly visualized\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Demonstrated that CHMP2A lacks intrinsic lipid specificity and requires CHMP3 for membrane binding, defining its biophysical role relative to the membrane-rigidifying CHMP2B paralog.\",\n      \"evidence\": \"In vitro reconstitution with purified proteins on biomimetic membranes and membrane mechanics measurements\",\n      \"pmids\": [\"33832485\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not establish the filament architecture underlying binding\", \"Physiological membrane substrate composition not addressed\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Reduced the subunit to three minimal functional requirements\\u2014spiral formation, lateral heteropolymerization, and VPS4 binding\\u2014using the yeast ortholog, defining the conserved logic of ESCRT-III function.\",\n      \"evidence\": \"Mutagenesis, genetic complementation, and engineered selection in S. cerevisiae Vps2\",\n      \"pmids\": [\"34028356\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Inferred from yeast ortholog rather than human CHMP2A\", \"Did not test membrane fission directly\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Positioned CHMP2A downstream of PTEN in autophagy regulation, showing CHMP2A is required for PTEN-mediated autophagy flux and tissue protection after ischemia/reperfusion.\",\n      \"evidence\": \"PTEN transgenic mice, proteomics, CHMP2A siRNA rescue, autophagy flux assays\",\n      \"pmids\": [\"34789720\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism by which PTEN upregulates CHMP2A unclear\", \"Direct role of CHMP2A in autolysosome formation not visualized\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Identified CHMP2A as a tumor immune-evasion factor that suppresses NF-\\u03baB-driven chemokine secretion and drives NK-cell-killing via MICA/B- and TRAIL-bearing extracellular vesicles.\",\n      \"evidence\": \"Genome-wide CRISPR screen, CHMP2A KO, NF-\\u03baB analysis, EV characterization, NK killing assays, xenografts\",\n      \"pmids\": [\"35393416\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"How ESCRT-III membrane activity connects mechanistically to NF-\\u03baB is unresolved\", \"EV cargo loading mechanism not defined\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Provided the atomic structural mechanism: CHMP2A-CHMP3 open-conformation heterodimers form helical membrane-coating filaments cleaved by VPS4, establishing CHMP2A-CHMP3-VPS4 as a minimal fission machine.\",\n      \"evidence\": \"Cryo-EM at 3.3/3.6 \\u00c5, high-speed AFM, fluorescence microscopy\",\n      \"pmids\": [\"36604498\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"In-cell relevance of the reconstituted geometry not tested\", \"Stoichiometry with other ESCRT-III subunits in physiological filaments unresolved\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Extended the immune-evasion role in vivo, showing CHMP2A loss broadens antitumor immunity (more T and NK cells, fewer MDSCs) and confirmed the effect is immune-dependent.\",\n      \"evidence\": \"CRISPR KO, syngeneic immunocompetent vs immunodeficient orthotopic transplantation, immune profiling\",\n      \"pmids\": [\"38702144\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Cell-intrinsic mechanism altering MDSC and T-cell recruitment not defined\", \"Whether effect is EV-dependent in vivo not isolated\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Began mapping CHMP2A lipid environment during division by capturing associated lipid species in dividing cells.\",\n      \"evidence\": \"Lipid-trap mass spectrometry (GFP-CHMP2A IP plus lipidomics) in dividing HeLa cells (preprint)\",\n      \"pmids\": [\"bio_10.1101_2024.12.13.627510\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Single method, preprint, no functional validation of specific lipid interactions\", \"Direct binding vs co-purification not distinguished\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Defined CHMP2A as a hierarchical organizer of abscission, with downstream ESCRT-III subunits depending on it for correct localization while abscission is delayed rather than abolished.\",\n      \"evidence\": \"Live imaging, SIM, correlative light-electron microscopy in CHMP2A KO cells\",\n      \"pmids\": [\"40928930\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Redundancy compensating for CHMP2A loss not identified\", \"Order of subunit recruitment relative to VPS4 not fully resolved\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How CHMP2A's membrane-fission activity is mechanistically coupled to its signaling roles (NF-\\u03baB modulation, EV-mediated immune suppression, PTEN-dependent autophagy) remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No direct link established between filament/fission activity and NF-\\u03baB control\", \"Mechanism of immune-relevant EV biogenesis by CHMP2A undefined\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0005198\", \"supporting_discovery_ids\": [0, 1, 6]},\n      {\"term_id\": \"GO:0008289\", \"supporting_discovery_ids\": [1]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005768\", \"supporting_discovery_ids\": [2]},\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [0, 1]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1640170\", \"supporting_discovery_ids\": [6]},\n      {\"term_id\": \"R-HSA-9612973\", \"supporting_discovery_ids\": [4, 8]},\n      {\"term_id\": \"R-HSA-5653656\", \"supporting_discovery_ids\": [0]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [5, 7]}\n    ],\n    \"complexes\": [\"ESCRT-III\"],\n    \"partners\": [\"CHMP3\", \"VPS4B\", \"CHMP4B\", \"CHMP1B\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":7,"faith_pct":100.0}}