{"gene":"CHMP4C","run_date":"2026-06-09T22:57:18","timeline":{"discoveries":[{"year":2012,"finding":"CHMP4C, an ESCRT-III subunit, functions in the Aurora B-dependent abscission checkpoint to prevent premature cytokinetic abscission. CHMP4C interacts with Borealin (a component of the chromosomal passenger complex, CPC), and Aurora B phosphorylates CHMP4C to inhibit abscission, thereby protecting against DNA damage during chromosome bridge resolution.","method":"Co-immunoprecipitation (interaction with Borealin/CPC), loss-of-function (depletion phenotype: premature abscission and DNA damage), spatiotemporal localization during cytokinesis","journal":"Science","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP establishing Borealin interaction, loss-of-function with defined phenotype, replicated and extended by multiple subsequent studies","pmids":["22422861"],"is_preprint":false},{"year":2016,"finding":"CHMP4C binds to and remodels membranes in vitro; Borealin prevents the association of CHMP4C with membranes, while Aurora B phosphorylation interferes with CHMP4C's membrane remodelling activity but not its assembly into spiral filaments at the abscission site. Gradual dephosphorylation of CHMP4C triggers a relay between the CPC and the centralspindlin complex (which preferentially associates with unphosphorylated CHMP4C) to regulate CHMP4C distribution and activation for abscission.","method":"Atomic force microscopy (membrane binding and remodeling in vitro), CHMP4C interactome in telophase cells (MS/Co-IP), co-immunoprecipitation with centralspindlin, phospho-mutant analysis","journal":"Open Biology","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — in vitro reconstitution of membrane remodeling combined with interactome and Co-IP, multiple orthogonal methods in single lab","pmids":["27784789"],"is_preprint":false},{"year":2018,"finding":"CHMP4C localizes to prometaphase kinetochores and is required for mitotic spindle checkpoint signaling. CHMP4C binds directly to ZW10 through a small C-terminal region, promotes localization of the RZZ complex (Rod-ZW10-Zwilch) and Mad1-Mad2 checkpoint proteins to unattached kinetochores, and is required for mitotic arrest upon microtubule depolymerization. Constitutive CHMP4C kinetochore targeting causes a ZW10-dependent checkpoint arrest. This function does not require ESCRT-dependent membrane remodeling.","method":"siRNA depletion, Co-immunoprecipitation (ZW10 binding), live imaging, constitutive kinetochore targeting experiments, nocodazole-induced checkpoint assay","journal":"Journal of Cell Biology","confidence":"High","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP for ZW10 interaction, loss-of-function with defined kinetochore/checkpoint phenotype, domain mapping, constitutive targeting rescue, multiple orthogonal methods in single lab","pmids":["29362225"],"is_preprint":false},{"year":2018,"finding":"CHMP4C associates with NDC80 complex components Hec1 and Nuf2 and is required for optimal NDC80 stability and Hec1-Nuf2 localization to prometaphase kinetochores. Nuf2 is required for CHMP4C kinetochore targeting. CHMP4C also binds tubulin in cell extracts and directly binds and bundles microtubules in vitro through its highly basic N-terminal region (amino acids 1–77). This N-terminal region is required for cold-stable kinetochore microtubules and efficient chromosome alignment.","method":"Co-immunoprecipitation (Hec1, Nuf2), in vitro microtubule binding and bundling assay, domain mutagenesis (N-terminal region), siRNA depletion with constitutive targeting rescue","journal":"Chromosoma","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — in vitro microtubule binding reconstitution, Co-IP with NDC80 components, domain mutagenesis, multiple orthogonal methods in single lab","pmids":["29968190"],"is_preprint":false},{"year":2015,"finding":"Radiation-induced Aurora B expression enhances CHMP4C phosphorylation in non-small cell lung cancer cells, which maintains cell cycle checkpoint and cellular viability and mediates radiation resistance. CHMP4C depletion delays S-phase, reduces IR-induced γH2AX foci formation, and sensitizes cells to radiation; inhibition of Aurora B mimics CHMP4C silencing. This Aurora B–CHMP4C axis operates independently of p53 status.","method":"siRNA depletion, Western blot (phosphorylation), colony formation assay, flow cytometry (cell cycle), γH2AX/53BP1 foci fluorescence microscopy, Aurora B inhibitor","journal":"International Journal of Molecular Sciences","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — loss-of-function with multiple readouts, Aurora B inhibitor phenocopy, but no direct phosphorylation mapping or mutagenesis; single lab","pmids":["26712741"],"is_preprint":false},{"year":2020,"finding":"CHMP4C is required for midbody remnant (MBR) inheritance by polarized epithelial cells. Its depletion dramatically reduces MBR inheritance and the percentage of ciliated cells. Correlative light and ultra-high-resolution scanning electron microscopy revealed a membranous stalk connecting the MBR to the apical plasma membrane, and CHMP4C maintains the integrity of this connection.","method":"Correlative light and ultra-high-resolution scanning electron microscopy, siRNA depletion, ciliation assay","journal":"iScience","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct structural imaging combined with loss-of-function and functional readout (ciliation), single lab","pmids":["32629610"],"is_preprint":false},{"year":2021,"finding":"CHMP4C localizes specifically to recycling endosomes and is required for membrane fission of recycling endocytic tubules. Depletion of CHMP4C (but not paralogs CHMP4A or CHMP4B) causes extensive tubulation of transferrin receptor-positive recycling endosomes, failure of fission, and impaired HSV1 envelopment.","method":"siRNA library screen, ultrastructural (electron) and confocal microscopy, virus production assay, exogenous CHMP4C localization to recycling endosomes","journal":"mBio","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — ultrastructural microscopy of fission defect, paralog-specificity tested, functional virus production readout; single lab, no in vitro reconstitution","pmids":["33975940"],"is_preprint":false},{"year":2023,"finding":"CHMP4C directly interacts with EGFR and promotes lysosome-mediated degradation of activated EGFR in cardiomyocytes, thereby attenuating cardiac hypertrophy. CHMP4C knockout exacerbates pressure-overload cardiac hypertrophy, while cardiomyocyte-specific overexpression attenuates it. An EGFR inhibitor counteracts the exacerbation caused by CHMP4C knockdown.","method":"Co-immunoprecipitation, confocal imaging (colocalization), CHMP4C knockout and cardiac-specific overexpression mouse models, transverse aortic constriction, EGFR inhibitor rescue","journal":"Hypertension","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP plus genetic KO/OE in vivo with defined phenotype and pharmacological rescue; single lab, no in vitro reconstitution","pmids":["37846580"],"is_preprint":false},{"year":2025,"finding":"CHMP4C regulates angiogenesis in endothelial cells by modulating endocytic trafficking of GSK3β. CHMP4C deficiency impedes endocytic trafficking of GSK3β, leading to hyperactivation of GSK3β, repression of the Wnt/β-catenin pathway, G1/S cell cycle arrest, and impaired angiogenesis in vitro and in vivo. Selective GSK3β inhibition rescues the proliferative defects caused by CHMP4C deficiency.","method":"CHMP4C knockout mice (hind-limb ischemia model), siRNA knockdown, RNA-Seq, electron microscopy and immunohistochemical colocalization, GSK3β inhibitor rescue","journal":"FASEB Journal","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — in vivo KO model with functional readout, mechanistic pathway identification by RNA-Seq and colocalization, pharmacological rescue; single lab","pmids":["41195682"],"is_preprint":false},{"year":2025,"finding":"CHMP4C interacts with YBX1 to mediate m5C modification of caspase-8 mRNA, resulting in increased caspase-8 expression and inhibition of RIPK1/RIPK3/MLKL pathway phosphorylation (necroptosis suppression). CHMP4C also promotes extracellular exocytosis of phospho-MLKL to further suppress necroptosis in pancreatic cancer cells.","method":"RNA immunoprecipitation, MeRIP-qPCR, co-immunoprecipitation (YBX1), differential ultracentrifugation (extracellular vesicle isolation), in vitro and in vivo functional assays","journal":"Journal of Advanced Research","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — Co-IP for YBX1 interaction, MeRIP for m5C modification, multiple orthogonal methods; single lab, novel mechanism with limited replication","pmids":["39870301"],"is_preprint":false}],"current_model":"CHMP4C is an ESCRT-III subunit that functions in multiple cellular contexts: during cytokinesis, it is phosphorylated by Aurora B kinase and interacts with the chromosomal passenger complex (via Borealin) and centralspindlin to regulate abscission timing and the abscission checkpoint; at kinetochores, it binds ZW10 and NDC80 complex components (Hec1, Nuf2), directly bundles microtubules via its N-terminal region, and promotes RZZ-dependent spindle checkpoint signaling; it also facilitates midbody remnant inheritance, maintains recycling endosome fission integrity, targets activated EGFR and GSK3β for endocytic/lysosomal degradation, and suppresses necroptosis via a YBX1-mediated m5C modification of caspase-8 mRNA."},"narrative":{"mechanistic_narrative":"CHMP4C is an ESCRT-III subunit that times the final membrane-scission step of cytokinesis through the Aurora B-dependent abscission checkpoint, coupling abscission to faithful chromosome segregation [PMID:22422861]. It interacts with the chromosomal passenger complex via Borealin, and Aurora B phosphorylation of CHMP4C interferes with its membrane-remodeling activity while leaving its assembly into spiral filaments at the abscission site intact; gradual dephosphorylation hands CHMP4C from the CPC to centralspindlin, which preferentially binds the unphosphorylated form to license abscission [PMID:22422861, PMID:27784789]. Beyond cytokinesis, CHMP4C carries out an ESCRT-independent role at prometaphase kinetochores, binding ZW10 directly and associating with the NDC80 components Hec1 and Nuf2 to promote RZZ and Mad1-Mad2 recruitment and the spindle assembly checkpoint, and it directly bundles microtubules through its basic N-terminal region (residues 1–77) to support cold-stable kinetochore fibers and chromosome alignment [PMID:29362225, PMID:29968190]. CHMP4C also acts in membrane-trafficking contexts: it is required for fission of transferrin receptor-positive recycling endosome tubules, an activity not shared by its paralogs CHMP4A/B, and for midbody remnant inheritance and ciliation in epithelial cells [PMID:32629610, PMID:33975940]. In differentiated tissues it directs endocytic/lysosomal fate of signaling receptors—promoting lysosomal degradation of activated EGFR to limit cardiac hypertrophy and modulating GSK3β endocytic trafficking to sustain Wnt/β-catenin signaling and angiogenesis [PMID:37846580, PMID:41195682]. In pancreatic cancer cells it suppresses necroptosis by partnering with YBX1 to deposit m5C on caspase-8 mRNA and by promoting exocytosis of phospho-MLKL [PMID:39870301].","teleology":[{"year":2012,"claim":"Established CHMP4C as the ESCRT-III subunit that enforces an abscission checkpoint, answering how cytokinesis is delayed when chromatin remains in the cleavage plane.","evidence":"Co-IP with Borealin/CPC, loss-of-function showing premature abscission and DNA damage, and spatiotemporal localization during cytokinesis","pmids":["22422861"],"confidence":"High","gaps":["Did not resolve the in vitro biochemical consequence of Aurora B phosphorylation","Phosphosite-to-mechanism link not mapped structurally"]},{"year":2016,"claim":"Defined the biochemical logic of the checkpoint: phosphorylation gates membrane remodeling (not filament assembly), and a CPC-to-centralspindlin relay reads CHMP4C phosphostate to time activation.","evidence":"Atomic force microscopy of membrane binding/remodeling in vitro, telophase interactome by MS/Co-IP, centralspindlin Co-IP, and phospho-mutant analysis","pmids":["27784789"],"confidence":"High","gaps":["Structural basis of phospho-dependent remodeling inhibition not solved","How dephosphorylation kinetics are controlled in vivo unclear"]},{"year":2018,"claim":"Revealed an ESCRT-independent kinetochore function: CHMP4C binds ZW10 and promotes RZZ/Mad1-Mad2 recruitment to drive the spindle assembly checkpoint, expanding its role beyond membrane scission.","evidence":"siRNA depletion, ZW10 Co-IP, domain mapping, constitutive kinetochore targeting, and nocodazole checkpoint assay","pmids":["29362225"],"confidence":"High","gaps":["How CHMP4C is recruited to kinetochores not fully defined here","Relationship between kinetochore pool and cytokinetic pool unaddressed"]},{"year":2018,"claim":"Connected CHMP4C to the NDC80 complex and identified a direct microtubule-bundling activity in its N-terminal basic region, explaining its contribution to kinetochore-microtubule stability and chromosome alignment.","evidence":"Co-IP with Hec1/Nuf2, in vitro microtubule binding/bundling assay, N-terminal domain mutagenesis, and depletion-rescue","pmids":["29968190"],"confidence":"High","gaps":["Whether microtubule bundling is regulated by Aurora B phosphorylation untested","Stoichiometry of CHMP4C within the kinetochore not defined"]},{"year":2015,"claim":"Showed the Aurora B–CHMP4C axis confers radiation resistance independent of p53, linking the checkpoint role to cancer cell survival.","evidence":"siRNA depletion, phospho Western blot, colony formation, cell-cycle flow cytometry, γH2AX/53BP1 foci, and Aurora B inhibitor in NSCLC cells","pmids":["26712741"],"confidence":"Medium","gaps":["No direct phosphosite mapping or mutagenesis","Single lung-cancer model; generality untested"]},{"year":2020,"claim":"Demonstrated CHMP4C is required for midbody remnant inheritance and ciliation, tying its membrane activity to a structural connection at the apical surface.","evidence":"Correlative light and ultra-high-resolution scanning EM, siRNA depletion, and ciliation assay","pmids":["32629610"],"confidence":"Medium","gaps":["Molecular partners maintaining the membranous stalk not identified","Single epithelial system"]},{"year":2021,"claim":"Identified a paralog-specific role for CHMP4C in fission of recycling endosome tubules, distinguishing it functionally from CHMP4A/CHMP4B.","evidence":"siRNA screen, EM and confocal microscopy of tubulation/fission defect, HSV1 envelopment assay, and exogenous localization to recycling endosomes","pmids":["33975940"],"confidence":"Medium","gaps":["No in vitro reconstitution of the fission reaction","Adaptors targeting CHMP4C to recycling endosomes unknown"]},{"year":2023,"claim":"Placed CHMP4C in receptor-degradation control by showing it drives lysosomal degradation of activated EGFR to restrain cardiac hypertrophy.","evidence":"Co-IP, colocalization imaging, CHMP4C KO and cardiac-specific overexpression mice with transverse aortic constriction, and EGFR inhibitor rescue","pmids":["37846580"],"confidence":"Medium","gaps":["No in vitro reconstitution of EGFR sorting","Whether ESCRT-III machinery is engaged here not dissected"]},{"year":2025,"claim":"Extended the trafficking role to GSK3β, showing CHMP4C-dependent endocytic trafficking restrains GSK3β activity to sustain Wnt/β-catenin signaling and angiogenesis.","evidence":"CHMP4C KO mice (hind-limb ischemia), siRNA knockdown, RNA-Seq, EM/IHC colocalization, and GSK3β inhibitor rescue","pmids":["41195682"],"confidence":"Medium","gaps":["Direct CHMP4C–GSK3β physical interaction not established","Mechanism of GSK3β trafficking step unresolved"]},{"year":2025,"claim":"Uncovered an RNA-modification role: CHMP4C partners with YBX1 to deposit m5C on caspase-8 mRNA and promotes phospho-MLKL exocytosis, suppressing necroptosis in pancreatic cancer.","evidence":"RNA-IP, MeRIP-qPCR, YBX1 Co-IP, differential ultracentrifugation for EVs, and in vitro/in vivo functional assays","pmids":["39870301"],"confidence":"Medium","gaps":["Whether CHMP4C has intrinsic RNA-binding/m5C activity versus a scaffolding role unclear","Single cancer model; replication limited"]},{"year":null,"claim":"How a single ESCRT-III subunit coordinates its membrane-scission, microtubule-bundling, receptor-sorting, and RNA-modification roles—and which interactions partition it among these functions—remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unifying structural model links the diverse activities","Regulation switching CHMP4C between kinetochore, endosomal, and abscission pools not defined"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0008092","term_label":"cytoskeletal protein binding","supporting_discovery_ids":[3]},{"term_id":"GO:0005198","term_label":"structural molecule activity","supporting_discovery_ids":[1,6]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[0,2]}],"localization":[{"term_id":"GO:0005768","term_label":"endosome","supporting_discovery_ids":[6,8]},{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[1,5]},{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[2,3]}],"pathway":[{"term_id":"R-HSA-1640170","term_label":"Cell Cycle","supporting_discovery_ids":[0,2,3]},{"term_id":"R-HSA-9609507","term_label":"Protein localization","supporting_discovery_ids":[6,7,8]},{"term_id":"R-HSA-5357801","term_label":"Programmed Cell Death","supporting_discovery_ids":[9]},{"term_id":"R-HSA-5653656","term_label":"Vesicle-mediated transport","supporting_discovery_ids":[5,6]}],"complexes":["ESCRT-III"],"partners":["BOREALIN","ZW10","HEC1","NUF2","EGFR","YBX1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q96CF2","full_name":"Charged multivesicular body protein 4c","aliases":["Chromatin-modifying protein 4c","CHMP4c","SNF7 homolog associated with Alix 3","SNF7-3","hSnf7-3","Vacuolar protein sorting-associated protein 32-3","Vps32-3","hVps32-3"],"length_aa":233,"mass_kda":26.4,"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 and the budding of enveloped viruses (HIV-1 and other lentiviruses). Key component of the cytokinesis checkpoint, a process required to delay abscission to prevent both premature resolution of intercellular chromosome bridges and accumulation of DNA damage: upon phosphorylation by AURKB, together with ZFYVE19/ANCHR, retains abscission-competent VPS4 (VPS4A and/or VPS4B) at the midbody ring until abscission checkpoint signaling is terminated at late cytokinesis. Deactivation of AURKB results in dephosphorylation of CHMP4C followed by its dissociation from ANCHR and VPS4 and subsequent abscission (PubMed:22422861, PubMed:24814515). ESCRT-III proteins are believed to mediate the necessary vesicle extrusion and/or membrane fission activities, possibly in conjunction with the AAA ATPase VPS4. Involved in HIV-1 p6- and p9-dependent virus release. CHMP4A/B/C are required for the exosomal release of SDCBP, CD63 and syndecan (PubMed:22660413)","subcellular_location":"Cytoplasm, cytosol; Late endosome membrane; Midbody, Midbody ring","url":"https://www.uniprot.org/uniprotkb/Q96CF2/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/CHMP4C","classification":"Not Classified","n_dependent_lines":1,"n_total_lines":1208,"dependency_fraction":0.0008278145695364238},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/CHMP4C","total_profiled":1310},"omim":[{"mim_id":"619635","title":"ZINC FINGER FYVE DOMAIN-CONTAINING PROTEIN 19; ZFYVE19","url":"https://www.omim.org/entry/619635"},{"mim_id":"610899","title":"CHARGED MULTIVESICULAR BODY PROTEIN 4C; CHMP4C","url":"https://www.omim.org/entry/610899"},{"mim_id":"610897","title":"CHARGED MULTIVESICULAR BODY PROTEIN 4B; CHMP4B","url":"https://www.omim.org/entry/610897"},{"mim_id":"608074","title":"PROGRAMMED CELL DEATH 6-INTERACTING PROTEIN; PDCD6IP","url":"https://www.omim.org/entry/608074"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Microtubules","reliability":"Approved"},{"location":"Cytokinetic bridge","reliability":"Approved"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"intestine","ntpm":39.4}],"url":"https://www.proteinatlas.org/search/CHMP4C"},"hgnc":{"alias_symbol":["MGC22825","Shax3","VPS32C"],"prev_symbol":[]},"alphafold":{"accession":"Q96CF2","domains":[{"cath_id":"1.10.287.1060","chopping":"23-123","consensus_level":"high","plddt":94.1621,"start":23,"end":123},{"cath_id":"1.20.5","chopping":"125-155","consensus_level":"medium","plddt":77.2006,"start":125,"end":155}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q96CF2","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q96CF2-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q96CF2-F1-predicted_aligned_error_v6.png","plddt_mean":76.44},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=CHMP4C","jax_strain_url":"https://www.jax.org/strain/search?query=CHMP4C"},"sequence":{"accession":"Q96CF2","fasta_url":"https://rest.uniprot.org/uniprotkb/Q96CF2.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q96CF2/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q96CF2"}},"corpus_meta":[{"pmid":"22422861","id":"PMC_22422861","title":"ESCRT-III governs the Aurora B-mediated abscission checkpoint through CHMP4C.","date":"2012","source":"Science (New York, N.Y.)","url":"https://pubmed.ncbi.nlm.nih.gov/22422861","citation_count":250,"is_preprint":false},{"pmid":"27784789","id":"PMC_27784789","title":"Coordinated regulation of the ESCRT-III component CHMP4C by the chromosomal passenger complex and centralspindlin during cytokinesis.","date":"2016","source":"Open biology","url":"https://pubmed.ncbi.nlm.nih.gov/27784789","citation_count":34,"is_preprint":false},{"pmid":"32406588","id":"PMC_32406588","title":"Chromatin modified protein 4C (CHMP4C) facilitates the malignant development of cervical cancer cells.","date":"2020","source":"FEBS open bio","url":"https://pubmed.ncbi.nlm.nih.gov/32406588","citation_count":33,"is_preprint":false},{"pmid":"29362225","id":"PMC_29362225","title":"The ESCRT protein Chmp4c regulates mitotic spindle checkpoint signaling.","date":"2018","source":"The Journal of cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/29362225","citation_count":28,"is_preprint":false},{"pmid":"39870301","id":"PMC_39870301","title":"CHMP4C promotes pancreatic cancer progression by inhibiting necroptosis via the RIPK1/RIPK3/MLKL pathway.","date":"2025","source":"Journal of advanced research","url":"https://pubmed.ncbi.nlm.nih.gov/39870301","citation_count":22,"is_preprint":false},{"pmid":"34527317","id":"PMC_34527317","title":"CHMP4C regulates lung squamous carcinogenesis and progression through cell cycle pathway.","date":"2021","source":"Journal of thoracic disease","url":"https://pubmed.ncbi.nlm.nih.gov/34527317","citation_count":21,"is_preprint":false},{"pmid":"26712741","id":"PMC_26712741","title":"CHMP4C Disruption Sensitizes the Human Lung Cancer Cells to Irradiation.","date":"2015","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/26712741","citation_count":21,"is_preprint":false},{"pmid":"33975940","id":"PMC_33975940","title":"Novel Role for ESCRT-III Component CHMP4C in the Integrity of the Endocytic Network Utilized for Herpes Simplex Virus Envelopment.","date":"2021","source":"mBio","url":"https://pubmed.ncbi.nlm.nih.gov/33975940","citation_count":18,"is_preprint":false},{"pmid":"35342302","id":"PMC_35342302","title":"Identification of a Pyroptosis-Related Gene Signature and Effect of Silencing the CHMP4C and CASP4 in Pancreatic Adenocarcinoma.","date":"2022","source":"International journal of general medicine","url":"https://pubmed.ncbi.nlm.nih.gov/35342302","citation_count":15,"is_preprint":false},{"pmid":"37388224","id":"PMC_37388224","title":"CHMP4C as a novel marker regulates prostate cancer progression through cycle pathways and contributes to immunotherapy.","date":"2023","source":"Frontiers in oncology","url":"https://pubmed.ncbi.nlm.nih.gov/37388224","citation_count":11,"is_preprint":false},{"pmid":"32629610","id":"PMC_32629610","title":"Midbody Remnant Inheritance Is Regulated by the ESCRT Subunit CHMP4C.","date":"2020","source":"iScience","url":"https://pubmed.ncbi.nlm.nih.gov/32629610","citation_count":10,"is_preprint":false},{"pmid":"29968190","id":"PMC_29968190","title":"Chmp4c is required for stable kinetochore-microtubule attachments.","date":"2018","source":"Chromosoma","url":"https://pubmed.ncbi.nlm.nih.gov/29968190","citation_count":9,"is_preprint":false},{"pmid":"37846580","id":"PMC_37846580","title":"ESCRT-III Component CHMP4C Attenuates Cardiac Hypertrophy by Targeting the Endo-Lysosomal Degradation of EGFR.","date":"2023","source":"Hypertension (Dallas, Tex. : 1979)","url":"https://pubmed.ncbi.nlm.nih.gov/37846580","citation_count":8,"is_preprint":false},{"pmid":"30250900","id":"PMC_30250900","title":"CHMP4C: A novel regulator of the mitotic spindle checkpoint.","date":"2018","source":"Molecular & cellular oncology","url":"https://pubmed.ncbi.nlm.nih.gov/30250900","citation_count":8,"is_preprint":false},{"pmid":"37993600","id":"PMC_37993600","title":"Chromatin-modifying protein 4C (CHMP4C) affects breast cancer cell growth and doxorubicin resistance as a potential breast cancer therapeutic target.","date":"2023","source":"The Journal of antibiotics","url":"https://pubmed.ncbi.nlm.nih.gov/37993600","citation_count":4,"is_preprint":false},{"pmid":"39138470","id":"PMC_39138470","title":"Exploring the clinical and biological significance of the cell cycle-related gene CHMP4C in prostate cancer.","date":"2024","source":"BMC medical genomics","url":"https://pubmed.ncbi.nlm.nih.gov/39138470","citation_count":2,"is_preprint":false},{"pmid":"41195682","id":"PMC_41195682","title":"ESCRT-III Subunit CHMP4C Regulates Angiogenesis by Targeting Endocytic Trafficking of GSK3β.","date":"2025","source":"FASEB journal : official publication of the Federation of American Societies for Experimental Biology","url":"https://pubmed.ncbi.nlm.nih.gov/41195682","citation_count":0,"is_preprint":false},{"pmid":"41247919","id":"PMC_41247919","title":"CHMP4C promotes the malignant progression of bladder cancer by regulating the PI3K/AKT pathway.","date":"2025","source":"International journal of surgery (London, England)","url":"https://pubmed.ncbi.nlm.nih.gov/41247919","citation_count":0,"is_preprint":false},{"pmid":"41085696","id":"PMC_41085696","title":"CHMP4C deletion inhibits the proliferation and metastasis of hypopharyngeal squamous cell carcinoma through the Wnt/β-catenin/EMT signaling pathway.","date":"2025","source":"European archives of oto-rhino-laryngology : official journal of the European Federation of Oto-Rhino-Laryngological Societies (EUFOS) : affiliated with the German Society for Oto-Rhino-Laryngology - Head and Neck Surgery","url":"https://pubmed.ncbi.nlm.nih.gov/41085696","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":11836,"output_tokens":3038,"usd":0.040539,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":10479,"output_tokens":3794,"usd":0.073622,"stage2_stop_reason":"end_turn"},"total_usd":0.114161,"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\": 2012,\n      \"finding\": \"CHMP4C, an ESCRT-III subunit, functions in the Aurora B-dependent abscission checkpoint to prevent premature cytokinetic abscission. CHMP4C interacts with Borealin (a component of the chromosomal passenger complex, CPC), and Aurora B phosphorylates CHMP4C to inhibit abscission, thereby protecting against DNA damage during chromosome bridge resolution.\",\n      \"method\": \"Co-immunoprecipitation (interaction with Borealin/CPC), loss-of-function (depletion phenotype: premature abscission and DNA damage), spatiotemporal localization during cytokinesis\",\n      \"journal\": \"Science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP establishing Borealin interaction, loss-of-function with defined phenotype, replicated and extended by multiple subsequent studies\",\n      \"pmids\": [\"22422861\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"CHMP4C binds to and remodels membranes in vitro; Borealin prevents the association of CHMP4C with membranes, while Aurora B phosphorylation interferes with CHMP4C's membrane remodelling activity but not its assembly into spiral filaments at the abscission site. Gradual dephosphorylation of CHMP4C triggers a relay between the CPC and the centralspindlin complex (which preferentially associates with unphosphorylated CHMP4C) to regulate CHMP4C distribution and activation for abscission.\",\n      \"method\": \"Atomic force microscopy (membrane binding and remodeling in vitro), CHMP4C interactome in telophase cells (MS/Co-IP), co-immunoprecipitation with centralspindlin, phospho-mutant analysis\",\n      \"journal\": \"Open Biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — in vitro reconstitution of membrane remodeling combined with interactome and Co-IP, multiple orthogonal methods in single lab\",\n      \"pmids\": [\"27784789\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"CHMP4C localizes to prometaphase kinetochores and is required for mitotic spindle checkpoint signaling. CHMP4C binds directly to ZW10 through a small C-terminal region, promotes localization of the RZZ complex (Rod-ZW10-Zwilch) and Mad1-Mad2 checkpoint proteins to unattached kinetochores, and is required for mitotic arrest upon microtubule depolymerization. Constitutive CHMP4C kinetochore targeting causes a ZW10-dependent checkpoint arrest. This function does not require ESCRT-dependent membrane remodeling.\",\n      \"method\": \"siRNA depletion, Co-immunoprecipitation (ZW10 binding), live imaging, constitutive kinetochore targeting experiments, nocodazole-induced checkpoint assay\",\n      \"journal\": \"Journal of Cell Biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP for ZW10 interaction, loss-of-function with defined kinetochore/checkpoint phenotype, domain mapping, constitutive targeting rescue, multiple orthogonal methods in single lab\",\n      \"pmids\": [\"29362225\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"CHMP4C associates with NDC80 complex components Hec1 and Nuf2 and is required for optimal NDC80 stability and Hec1-Nuf2 localization to prometaphase kinetochores. Nuf2 is required for CHMP4C kinetochore targeting. CHMP4C also binds tubulin in cell extracts and directly binds and bundles microtubules in vitro through its highly basic N-terminal region (amino acids 1–77). This N-terminal region is required for cold-stable kinetochore microtubules and efficient chromosome alignment.\",\n      \"method\": \"Co-immunoprecipitation (Hec1, Nuf2), in vitro microtubule binding and bundling assay, domain mutagenesis (N-terminal region), siRNA depletion with constitutive targeting rescue\",\n      \"journal\": \"Chromosoma\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — in vitro microtubule binding reconstitution, Co-IP with NDC80 components, domain mutagenesis, multiple orthogonal methods in single lab\",\n      \"pmids\": [\"29968190\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Radiation-induced Aurora B expression enhances CHMP4C phosphorylation in non-small cell lung cancer cells, which maintains cell cycle checkpoint and cellular viability and mediates radiation resistance. CHMP4C depletion delays S-phase, reduces IR-induced γH2AX foci formation, and sensitizes cells to radiation; inhibition of Aurora B mimics CHMP4C silencing. This Aurora B–CHMP4C axis operates independently of p53 status.\",\n      \"method\": \"siRNA depletion, Western blot (phosphorylation), colony formation assay, flow cytometry (cell cycle), γH2AX/53BP1 foci fluorescence microscopy, Aurora B inhibitor\",\n      \"journal\": \"International Journal of Molecular Sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — loss-of-function with multiple readouts, Aurora B inhibitor phenocopy, but no direct phosphorylation mapping or mutagenesis; single lab\",\n      \"pmids\": [\"26712741\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"CHMP4C is required for midbody remnant (MBR) inheritance by polarized epithelial cells. Its depletion dramatically reduces MBR inheritance and the percentage of ciliated cells. Correlative light and ultra-high-resolution scanning electron microscopy revealed a membranous stalk connecting the MBR to the apical plasma membrane, and CHMP4C maintains the integrity of this connection.\",\n      \"method\": \"Correlative light and ultra-high-resolution scanning electron microscopy, siRNA depletion, ciliation assay\",\n      \"journal\": \"iScience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct structural imaging combined with loss-of-function and functional readout (ciliation), single lab\",\n      \"pmids\": [\"32629610\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"CHMP4C localizes specifically to recycling endosomes and is required for membrane fission of recycling endocytic tubules. Depletion of CHMP4C (but not paralogs CHMP4A or CHMP4B) causes extensive tubulation of transferrin receptor-positive recycling endosomes, failure of fission, and impaired HSV1 envelopment.\",\n      \"method\": \"siRNA library screen, ultrastructural (electron) and confocal microscopy, virus production assay, exogenous CHMP4C localization to recycling endosomes\",\n      \"journal\": \"mBio\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — ultrastructural microscopy of fission defect, paralog-specificity tested, functional virus production readout; single lab, no in vitro reconstitution\",\n      \"pmids\": [\"33975940\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"CHMP4C directly interacts with EGFR and promotes lysosome-mediated degradation of activated EGFR in cardiomyocytes, thereby attenuating cardiac hypertrophy. CHMP4C knockout exacerbates pressure-overload cardiac hypertrophy, while cardiomyocyte-specific overexpression attenuates it. An EGFR inhibitor counteracts the exacerbation caused by CHMP4C knockdown.\",\n      \"method\": \"Co-immunoprecipitation, confocal imaging (colocalization), CHMP4C knockout and cardiac-specific overexpression mouse models, transverse aortic constriction, EGFR inhibitor rescue\",\n      \"journal\": \"Hypertension\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP plus genetic KO/OE in vivo with defined phenotype and pharmacological rescue; single lab, no in vitro reconstitution\",\n      \"pmids\": [\"37846580\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"CHMP4C regulates angiogenesis in endothelial cells by modulating endocytic trafficking of GSK3β. CHMP4C deficiency impedes endocytic trafficking of GSK3β, leading to hyperactivation of GSK3β, repression of the Wnt/β-catenin pathway, G1/S cell cycle arrest, and impaired angiogenesis in vitro and in vivo. Selective GSK3β inhibition rescues the proliferative defects caused by CHMP4C deficiency.\",\n      \"method\": \"CHMP4C knockout mice (hind-limb ischemia model), siRNA knockdown, RNA-Seq, electron microscopy and immunohistochemical colocalization, GSK3β inhibitor rescue\",\n      \"journal\": \"FASEB Journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — in vivo KO model with functional readout, mechanistic pathway identification by RNA-Seq and colocalization, pharmacological rescue; single lab\",\n      \"pmids\": [\"41195682\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"CHMP4C interacts with YBX1 to mediate m5C modification of caspase-8 mRNA, resulting in increased caspase-8 expression and inhibition of RIPK1/RIPK3/MLKL pathway phosphorylation (necroptosis suppression). CHMP4C also promotes extracellular exocytosis of phospho-MLKL to further suppress necroptosis in pancreatic cancer cells.\",\n      \"method\": \"RNA immunoprecipitation, MeRIP-qPCR, co-immunoprecipitation (YBX1), differential ultracentrifugation (extracellular vesicle isolation), in vitro and in vivo functional assays\",\n      \"journal\": \"Journal of Advanced Research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — Co-IP for YBX1 interaction, MeRIP for m5C modification, multiple orthogonal methods; single lab, novel mechanism with limited replication\",\n      \"pmids\": [\"39870301\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"CHMP4C is an ESCRT-III subunit that functions in multiple cellular contexts: during cytokinesis, it is phosphorylated by Aurora B kinase and interacts with the chromosomal passenger complex (via Borealin) and centralspindlin to regulate abscission timing and the abscission checkpoint; at kinetochores, it binds ZW10 and NDC80 complex components (Hec1, Nuf2), directly bundles microtubules via its N-terminal region, and promotes RZZ-dependent spindle checkpoint signaling; it also facilitates midbody remnant inheritance, maintains recycling endosome fission integrity, targets activated EGFR and GSK3β for endocytic/lysosomal degradation, and suppresses necroptosis via a YBX1-mediated m5C modification of caspase-8 mRNA.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"CHMP4C is an ESCRT-III subunit that times the final membrane-scission step of cytokinesis through the Aurora B-dependent abscission checkpoint, coupling abscission to faithful chromosome segregation [#0]. It interacts with the chromosomal passenger complex via Borealin, and Aurora B phosphorylation of CHMP4C interferes with its membrane-remodeling activity while leaving its assembly into spiral filaments at the abscission site intact; gradual dephosphorylation hands CHMP4C from the CPC to centralspindlin, which preferentially binds the unphosphorylated form to license abscission [#0, #1]. Beyond cytokinesis, CHMP4C carries out an ESCRT-independent role at prometaphase kinetochores, binding ZW10 directly and associating with the NDC80 components Hec1 and Nuf2 to promote RZZ and Mad1-Mad2 recruitment and the spindle assembly checkpoint, and it directly bundles microtubules through its basic N-terminal region (residues 1\\u201377) to support cold-stable kinetochore fibers and chromosome alignment [#2, #3]. CHMP4C also acts in membrane-trafficking contexts: it is required for fission of transferrin receptor-positive recycling endosome tubules, an activity not shared by its paralogs CHMP4A/B, and for midbody remnant inheritance and ciliation in epithelial cells [#5, #6]. In differentiated tissues it directs endocytic/lysosomal fate of signaling receptors\\u2014promoting lysosomal degradation of activated EGFR to limit cardiac hypertrophy and modulating GSK3\\u03b2 endocytic trafficking to sustain Wnt/\\u03b2-catenin signaling and angiogenesis [#7, #8]. In pancreatic cancer cells it suppresses necroptosis by partnering with YBX1 to deposit m5C on caspase-8 mRNA and by promoting exocytosis of phospho-MLKL [#9].\",\n  \"teleology\": [\n    {\n      \"year\": 2012,\n      \"claim\": \"Established CHMP4C as the ESCRT-III subunit that enforces an abscission checkpoint, answering how cytokinesis is delayed when chromatin remains in the cleavage plane.\",\n      \"evidence\": \"Co-IP with Borealin/CPC, loss-of-function showing premature abscission and DNA damage, and spatiotemporal localization during cytokinesis\",\n      \"pmids\": [\"22422861\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not resolve the in vitro biochemical consequence of Aurora B phosphorylation\", \"Phosphosite-to-mechanism link not mapped structurally\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Defined the biochemical logic of the checkpoint: phosphorylation gates membrane remodeling (not filament assembly), and a CPC-to-centralspindlin relay reads CHMP4C phosphostate to time activation.\",\n      \"evidence\": \"Atomic force microscopy of membrane binding/remodeling in vitro, telophase interactome by MS/Co-IP, centralspindlin Co-IP, and phospho-mutant analysis\",\n      \"pmids\": [\"27784789\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of phospho-dependent remodeling inhibition not solved\", \"How dephosphorylation kinetics are controlled in vivo unclear\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Revealed an ESCRT-independent kinetochore function: CHMP4C binds ZW10 and promotes RZZ/Mad1-Mad2 recruitment to drive the spindle assembly checkpoint, expanding its role beyond membrane scission.\",\n      \"evidence\": \"siRNA depletion, ZW10 Co-IP, domain mapping, constitutive kinetochore targeting, and nocodazole checkpoint assay\",\n      \"pmids\": [\"29362225\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How CHMP4C is recruited to kinetochores not fully defined here\", \"Relationship between kinetochore pool and cytokinetic pool unaddressed\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Connected CHMP4C to the NDC80 complex and identified a direct microtubule-bundling activity in its N-terminal basic region, explaining its contribution to kinetochore-microtubule stability and chromosome alignment.\",\n      \"evidence\": \"Co-IP with Hec1/Nuf2, in vitro microtubule binding/bundling assay, N-terminal domain mutagenesis, and depletion-rescue\",\n      \"pmids\": [\"29968190\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether microtubule bundling is regulated by Aurora B phosphorylation untested\", \"Stoichiometry of CHMP4C within the kinetochore not defined\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Showed the Aurora B\\u2013CHMP4C axis confers radiation resistance independent of p53, linking the checkpoint role to cancer cell survival.\",\n      \"evidence\": \"siRNA depletion, phospho Western blot, colony formation, cell-cycle flow cytometry, \\u03b3H2AX/53BP1 foci, and Aurora B inhibitor in NSCLC cells\",\n      \"pmids\": [\"26712741\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No direct phosphosite mapping or mutagenesis\", \"Single lung-cancer model; generality untested\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Demonstrated CHMP4C is required for midbody remnant inheritance and ciliation, tying its membrane activity to a structural connection at the apical surface.\",\n      \"evidence\": \"Correlative light and ultra-high-resolution scanning EM, siRNA depletion, and ciliation assay\",\n      \"pmids\": [\"32629610\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular partners maintaining the membranous stalk not identified\", \"Single epithelial system\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Identified a paralog-specific role for CHMP4C in fission of recycling endosome tubules, distinguishing it functionally from CHMP4A/CHMP4B.\",\n      \"evidence\": \"siRNA screen, EM and confocal microscopy of tubulation/fission defect, HSV1 envelopment assay, and exogenous localization to recycling endosomes\",\n      \"pmids\": [\"33975940\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No in vitro reconstitution of the fission reaction\", \"Adaptors targeting CHMP4C to recycling endosomes unknown\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Placed CHMP4C in receptor-degradation control by showing it drives lysosomal degradation of activated EGFR to restrain cardiac hypertrophy.\",\n      \"evidence\": \"Co-IP, colocalization imaging, CHMP4C KO and cardiac-specific overexpression mice with transverse aortic constriction, and EGFR inhibitor rescue\",\n      \"pmids\": [\"37846580\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No in vitro reconstitution of EGFR sorting\", \"Whether ESCRT-III machinery is engaged here not dissected\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Extended the trafficking role to GSK3\\u03b2, showing CHMP4C-dependent endocytic trafficking restrains GSK3\\u03b2 activity to sustain Wnt/\\u03b2-catenin signaling and angiogenesis.\",\n      \"evidence\": \"CHMP4C KO mice (hind-limb ischemia), siRNA knockdown, RNA-Seq, EM/IHC colocalization, and GSK3\\u03b2 inhibitor rescue\",\n      \"pmids\": [\"41195682\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct CHMP4C\\u2013GSK3\\u03b2 physical interaction not established\", \"Mechanism of GSK3\\u03b2 trafficking step unresolved\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Uncovered an RNA-modification role: CHMP4C partners with YBX1 to deposit m5C on caspase-8 mRNA and promotes phospho-MLKL exocytosis, suppressing necroptosis in pancreatic cancer.\",\n      \"evidence\": \"RNA-IP, MeRIP-qPCR, YBX1 Co-IP, differential ultracentrifugation for EVs, and in vitro/in vivo functional assays\",\n      \"pmids\": [\"39870301\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether CHMP4C has intrinsic RNA-binding/m5C activity versus a scaffolding role unclear\", \"Single cancer model; replication limited\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How a single ESCRT-III subunit coordinates its membrane-scission, microtubule-bundling, receptor-sorting, and RNA-modification roles\\u2014and which interactions partition it among these functions\\u2014remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unifying structural model links the diverse activities\", \"Regulation switching CHMP4C between kinetochore, endosomal, and abscission pools not defined\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0008092\", \"supporting_discovery_ids\": [3]},\n      {\"term_id\": \"GO:0005198\", \"supporting_discovery_ids\": [1, 6]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [0, 2]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005768\", \"supporting_discovery_ids\": [6, 8]},\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [1, 5]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [2, 3]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1640170\", \"supporting_discovery_ids\": [0, 2, 3]},\n      {\"term_id\": \"R-HSA-9609507\", \"supporting_discovery_ids\": [6, 7, 8]},\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [9]},\n      {\"term_id\": \"R-HSA-5653656\", \"supporting_discovery_ids\": [5, 6]}\n    ],\n    \"complexes\": [\"ESCRT-III\"],\n    \"partners\": [\"Borealin\", \"ZW10\", \"Hec1\", \"Nuf2\", \"EGFR\", \"YBX1\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}