{"gene":"CHMP4C","run_date":"2026-04-28T17:28:52","timeline":{"discoveries":[{"year":2012,"finding":"CHMP4C, a human ESCRT-III subunit, functions in the Aurora B-dependent abscission checkpoint to prevent premature cytokinetic abscission. CHMP4C engages the chromosomal passenger complex (CPC) via direct interaction with Borealin, and is phosphorylated by Aurora B, which inhibits abscission. CHMP4C shows differential spatiotemporal distribution during late cytokinesis consistent with this regulatory role.","method":"Co-immunoprecipitation (CHMP4C–Borealin interaction), phosphorylation assays, RNAi depletion with cytokinesis/DNA damage phenotypic readouts, live-cell imaging","journal":"Science","confidence":"High","confidence_rationale":"Tier 2 — reciprocal Co-IP plus functional epistasis, high citation count, replicated by subsequent studies","pmids":["22422861"],"is_preprint":false},{"year":2016,"finding":"CHMP4C binds to and remodels membranes in vitro; Borealin prevents CHMP4C membrane association, while Aurora B phosphorylation interferes with its membrane-remodelling activity without blocking spiral filament assembly at the abscission site. Two spatially distinct pools of phosphorylated CHMP4C exist during cytokinesis. The centralspindlin complex associates preferentially with unphosphorylated CHMP4C, suggesting a relay mechanism in which gradual dephosphorylation of CHMP4C transfers control from CPC to centralspindlin to trigger abscission.","method":"Atomic force microscopy (membrane binding/remodelling in vitro), co-immunoprecipitation (CHMP4C interactome in telophase), phospho-mutant analysis, fluorescence microscopy","journal":"Open Biology","confidence":"High","confidence_rationale":"Tier 1–2 — in vitro reconstitution of membrane remodelling combined with interactome Co-IP and phospho-mutant epistasis","pmids":["27784789"],"is_preprint":false},{"year":2018,"finding":"CHMP4C localizes to kinetochores in prometaphase and promotes localisation of the RZZ (Rod-ZW10-Zwilch) complex and Mad1-Mad2 checkpoint proteins to unattached kinetochores. CHMP4C binds directly to ZW10 through a small C-terminal region. Loss of CHMP4C impairs mitotic checkpoint arrest and causes chromosome misalignment/missegregation. Constitutive kinetochore targeting of CHMP4C causes a ZW10-dependent metaphase arrest. These functions do not require ESCRT-dependent membrane remodelling.","method":"RNAi depletion with mitotic checkpoint assays (nocodazole arrest), co-immunoprecipitation (CHMP4C–ZW10), live-cell imaging, constitutive kinetochore-tethering constructs","journal":"Journal of Cell Biology","confidence":"High","confidence_rationale":"Tier 2 — reciprocal Co-IP plus epistasis with ZW10-dependent checkpoint arrest, multiple orthogonal methods","pmids":["29362225"],"is_preprint":false},{"year":2018,"finding":"CHMP4C associates with NDC80 complex components Hec1 and Nuf2, and is required for optimal Hec1-Nuf2 kinetochore localisation in prometaphase. Nuf2 is required for CHMP4C kinetochore targeting. CHMP4C binds tubulin in cell extracts and directly binds and bundles microtubules in vitro through its highly basic N-terminal region (amino acids 1–77). The 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 assays, N-terminal deletion mutants, kinetochore-tethering rescue experiments","journal":"Chromosoma","confidence":"High","confidence_rationale":"Tier 1–2 — in vitro microtubule binding assay plus Co-IP and domain-mapping mutagenesis","pmids":["29968190"],"is_preprint":false},{"year":2020,"finding":"CHMP4C enables midbody remnant (MBR) inheritance by maintaining the integrity of a membranous stalk connecting the MBR to the apical plasma membrane of epithelial cells. Depletion of CHMP4C dramatically reduces the percentage of ciliated cells, linking MBR inheritance to primary cilium formation.","method":"Correlative light and ultra-high-resolution scanning electron microscopy, siRNA depletion with ciliation readout","journal":"iScience","confidence":"Medium","confidence_rationale":"Tier 2 — direct localization by high-resolution EM plus functional consequence (loss of ciliation), single study","pmids":["32629610"],"is_preprint":false},{"year":2021,"finding":"CHMP4C (but not paralogues CHMP4A or CHMP4B) is specifically required for integrity of the recycling endosomal network; its depletion causes extensive tubulation of transferrin receptor-positive recycling endosomes indicative of aberrant fission. Exogenous CHMP4C localises to recycling endosomes. This role in recycling endosome fission is distinct from its late-endocytic pathway function.","method":"siRNA depletion screen, ultrastructural electron microscopy, confocal microscopy (transferrin receptor co-localisation), virus production as biological readout","journal":"mBio","confidence":"Medium","confidence_rationale":"Tier 2 — direct localization to recycling endosomes with ultrastructural functional phenotype, single study with multiple methods","pmids":["33975940"],"is_preprint":false},{"year":2015,"finding":"Aurora B phosphorylates CHMP4C in response to ionising radiation in non-small cell lung cancer cells, maintaining cell cycle checkpoint and cellular viability; CHMP4C depletion enhances radiosensitivity, delays S-phase, and reduces IR-induced γH2AX foci formation in a p53-independent manner.","method":"Western blotting (phosphorylation), siRNA depletion, flow cytometry (cell cycle), colony formation assay, γH2AX/53BP1 foci immunofluorescence","journal":"International Journal of Molecular Sciences","confidence":"Medium","confidence_rationale":"Tier 2 — phosphorylation assay plus functional KD phenotypes, single lab, multiple orthogonal readouts","pmids":["26712741"],"is_preprint":false},{"year":2023,"finding":"CHMP4C directly interacts with EGFR and promotes lysosome-mediated degradation of activated EGFR in cardiomyocytes; CHMP4C knockout exacerbates pressure-overload-induced cardiac hypertrophy, while cardiomyocyte-specific overexpression attenuates it. The EGFR inhibitor canertinib counteracts the hypertrophy exacerbation caused by CHMP4C knockdown, confirming EGFR dependence.","method":"Co-immunoprecipitation (CHMP4C–EGFR), confocal fluorescent co-localisation, CHMP4C knockout and cardiac-specific overexpression mouse models, EGFR inhibitor rescue","journal":"Hypertension","confidence":"Medium","confidence_rationale":"Tier 2 — Co-IP plus in vivo genetic models with pharmacological rescue, single study","pmids":["37846580"],"is_preprint":false},{"year":2025,"finding":"CHMP4C interacts with YBX1 to mediate m5C modification of caspase-8 mRNA, resulting in increased caspase-8 expression, which inhibits RIPK1/RIPK3/MLKL pathway phosphorylation and suppresses necroptosis in pancreatic cancer cells. CHMP4C also promotes exocytic secretion of phospho-MLKL via extracellular vesicles to further suppress necroptosis.","method":"RNA immunoprecipitation, MeRIP-qPCR (m5C methylation), co-immunoprecipitation (CHMP4C–YBX1), in vitro and in vivo functional assays, extracellular vesicle isolation","journal":"Journal of Advanced Research","confidence":"Medium","confidence_rationale":"Tier 2 — multiple biochemical methods (RIP, MeRIP, Co-IP) in a single study with in vivo validation","pmids":["39870301"],"is_preprint":false},{"year":2025,"finding":"CHMP4C deficiency in endothelial cells impairs endocytic trafficking of GSK3β, leading to GSK3β hyperactivation and repression of the Wnt/β-catenin pathway, causing G1/S arrest and impaired angiogenesis. Selective GSK3β inhibition rescues these defects.","method":"siRNA knockdown, RNA-Seq, electron microscopy and immunohistochemical co-localisation (GSK3β endocytic trafficking), CHMP4C knockout mouse hind-limb ischemia model, GSK3β inhibitor rescue","journal":"FASEB Journal","confidence":"Medium","confidence_rationale":"Tier 2 — direct ultrastructural evidence of trafficking defect plus in vivo KO and pharmacological rescue, single study","pmids":["41195682"],"is_preprint":false}],"current_model":"CHMP4C is an ESCRT-III subunit that is phosphorylated by Aurora B and functions as a checkpoint factor during cytokinetic abscission (via Borealin/CPC interaction and centralspindlin relay), promotes mitotic spindle checkpoint signaling by recruiting the RZZ complex to kinetochores through ZW10 binding, stabilizes kinetochore-microtubule attachments by associating with NDC80 components and directly bundling microtubules via its N-terminal domain, regulates midbody remnant inheritance and primary ciliogenesis, mediates fission of recycling endosomes, and in non-mitotic contexts promotes lysosomal degradation of membrane receptors such as EGFR and modulates endocytic trafficking of GSK3β to control Wnt/β-catenin signaling."},"narrative":{"teleology":[{"year":2012,"claim":"Establishing that CHMP4C functions as a checkpoint factor in cytokinetic abscission resolved how cells delay membrane scission when chromatin bridges persist: CHMP4C directly engages Borealin/CPC and is phosphorylated by Aurora B to inhibit abscission.","evidence":"Reciprocal co-immunoprecipitation of CHMP4C–Borealin, phosphorylation assays, RNAi with cytokinesis phenotypic readouts in human cells","pmids":["22422861"],"confidence":"High","gaps":["How CHMP4C phosphorylation mechanistically blocks membrane scission was not resolved","The downstream relay from CPC to abscission effectors was unclear"]},{"year":2015,"claim":"Demonstrating Aurora B-dependent CHMP4C phosphorylation after ionizing radiation extended its checkpoint role beyond cytokinesis, linking CHMP4C to DNA damage-induced cell cycle regulation and radiosensitivity in cancer cells.","evidence":"Western blotting for phospho-CHMP4C, siRNA depletion with flow cytometry and γH2AX foci quantification in NSCLC cells","pmids":["26712741"],"confidence":"Medium","gaps":["Mechanism by which CHMP4C influences γH2AX foci formation is unknown","Whether this reflects a direct DNA repair role or an indirect checkpoint effect was not distinguished","Single-lab finding, not independently replicated"]},{"year":2016,"claim":"Reconstituting CHMP4C membrane binding and remodeling in vitro, and showing that Borealin blocks membrane association while Aurora B phosphorylation inhibits remodeling activity, provided a biochemical mechanism for abscission delay and identified centralspindlin as the relay partner for triggering abscission upon CHMP4C dephosphorylation.","evidence":"Atomic force microscopy on supported lipid bilayers, co-immunoprecipitation of CHMP4C interactome in telophase, phospho-mutant analysis","pmids":["27784789"],"confidence":"High","gaps":["The phosphatase responsible for CHMP4C dephosphorylation was not identified","Whether the two spatially distinct phospho-CHMP4C pools have different functional outputs was not resolved"]},{"year":2018,"claim":"Identifying CHMP4C as a kinetochore-localized promoter of spindle assembly checkpoint signaling — via direct ZW10 binding and recruitment of the RZZ/Mad1-Mad2 module — revealed a mitotic function independent of its canonical ESCRT membrane role, and its N-terminal microtubule-bundling activity explained how it stabilizes kinetochore-microtubule attachments.","evidence":"RNAi with mitotic checkpoint assays, co-immunoprecipitation of CHMP4C–ZW10 and CHMP4C–Hec1/Nuf2, in vitro microtubule binding/bundling, constitutive kinetochore-tethering constructs","pmids":["29362225","29968190"],"confidence":"High","gaps":["How CHMP4C is regulated at kinetochores (e.g., whether Aurora B phosphorylation modulates its kinetochore functions) is unknown","Structural basis for CHMP4C–ZW10 interaction was not determined","Whether the kinetochore and cytokinesis pools of CHMP4C are sequentially regulated in mitosis remains unclear"]},{"year":2020,"claim":"Linking CHMP4C to midbody remnant inheritance and primary ciliogenesis showed that its abscission-related membrane function has downstream consequences for organelle biogenesis in epithelial cells.","evidence":"Correlative light and ultra-high-resolution scanning electron microscopy, siRNA depletion with ciliation readout","pmids":["32629610"],"confidence":"Medium","gaps":["The specific membrane topology CHMP4C maintains at the midbody stalk is not defined","Whether this ciliogenesis defect is solely due to MBR loss or involves additional CHMP4C functions was not tested","Single study without independent replication"]},{"year":2021,"claim":"Demonstrating that CHMP4C — uniquely among CHMP4 paralogues — is required for recycling endosome fission established a non-mitotic, paralogue-specific membrane scission role in the endosomal system.","evidence":"siRNA depletion screen, ultrastructural EM of tubulated recycling endosomes, confocal co-localization with transferrin receptor","pmids":["33975940"],"confidence":"Medium","gaps":["How CHMP4C is specifically recruited to recycling endosomes is unknown","Whether VPS4 is required for this fission event was not tested","Single study; independent confirmation is lacking"]},{"year":2023,"claim":"Showing that CHMP4C directly interacts with EGFR and promotes its lysosomal degradation provided a molecular link between ESCRT-III sorting and receptor downregulation, with in vivo relevance demonstrated by exacerbated cardiac hypertrophy in CHMP4C knockout mice rescued by EGFR inhibition.","evidence":"Co-immunoprecipitation of CHMP4C–EGFR, cardiac-specific overexpression and global knockout mouse models, EGFR inhibitor rescue","pmids":["37846580"],"confidence":"Medium","gaps":["Whether CHMP4C sorts other RTKs beyond EGFR is unknown","The mechanism distinguishing CHMP4C from other ESCRT-III subunits in EGFR degradation is not defined","Single study"]},{"year":2025,"claim":"Two studies expanded CHMP4C's non-mitotic repertoire: one showed CHMP4C regulates endocytic trafficking of GSK3β to control Wnt/β-catenin signaling and angiogenesis, and another revealed CHMP4C–YBX1-mediated m5C modification of caspase-8 mRNA to suppress necroptosis, with additional exocytic secretion of phospho-MLKL via extracellular vesicles.","evidence":"siRNA/KO with RNA-Seq and EM-based trafficking analysis plus GSK3β inhibitor rescue in endothelial cells and hind-limb ischemia model; RIP, MeRIP-qPCR, Co-IP of CHMP4C–YBX1, and EV isolation in pancreatic cancer cells with in vivo validation","pmids":["41195682","39870301"],"confidence":"Medium","gaps":["Whether CHMP4C's role in GSK3β trafficking involves its recycling endosome fission activity is not established","The CHMP4C–YBX1 interaction and m5C regulatory axis have not been independently replicated","How CHMP4C selectively packages phospho-MLKL into EVs is mechanistically undefined"]},{"year":null,"claim":"Major unresolved questions include how CHMP4C is differentially recruited to its distinct functional sites (kinetochores, midbody, recycling endosomes, late endosomes), what phosphatase reverses Aurora B phosphorylation to trigger abscission, whether CHMP4C's kinetochore and cytokinesis functions are coordinated during mitotic progression, and the structural basis for its paralogue-specific activities.","evidence":"","pmids":[],"confidence":"Low","gaps":["No structural model of CHMP4C–ZW10 or CHMP4C–Borealin complexes exists","Identity of CHMP4C phosphatase unknown","Basis for paralogue specificity (CHMP4C vs. CHMP4A/B) at recycling endosomes not determined"]}],"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":[1,3]}],"localization":[{"term_id":"GO:0005694","term_label":"chromosome","supporting_discovery_ids":[2,3]},{"term_id":"GO:0031410","term_label":"cytoplasmic vesicle","supporting_discovery_ids":[5,9]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[1]},{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[1,4]}],"pathway":[{"term_id":"R-HSA-1640170","term_label":"Cell Cycle","supporting_discovery_ids":[0,1,2,3]},{"term_id":"R-HSA-5653656","term_label":"Vesicle-mediated transport","supporting_discovery_ids":[5,7,9]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[7,9]},{"term_id":"R-HSA-1852241","term_label":"Organelle biogenesis and maintenance","supporting_discovery_ids":[4]}],"complexes":["ESCRT-III"],"partners":["BOREALIN","ZW10","HEC1","NUF2","EGFR","YBX1","GSK3B"],"other_free_text":[]},"mechanistic_narrative":"CHMP4C is an ESCRT-III subunit with multifaceted roles in cytokinesis, mitotic checkpoint signaling, endosomal membrane remodeling, and receptor trafficking. During cytokinesis, CHMP4C binds Borealin to engage the chromosomal passenger complex and is phosphorylated by Aurora B, which inhibits its membrane-remodeling activity and prevents premature abscission; dephosphorylation transfers control to centralspindlin, triggering abscission completion [PMID:22422861, PMID:27784789]. Independent of its ESCRT membrane-remodeling function, CHMP4C localizes to kinetochores via the NDC80 complex, recruits the RZZ checkpoint complex through direct ZW10 binding to sustain spindle assembly checkpoint signaling, and bundles microtubules through its basic N-terminal domain to stabilize kinetochore-microtubule attachments [PMID:29362225, PMID:29968190]. Beyond mitosis, CHMP4C mediates fission of recycling endosomes, promotes lysosomal degradation of activated EGFR, regulates endocytic trafficking of GSK3β to modulate Wnt/β-catenin signaling, and supports midbody remnant inheritance required for primary ciliogenesis [PMID:33975940, PMID:37846580, PMID:41195682, PMID:32629610]."},"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":"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":"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":17,"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":"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":"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":8,"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":"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":"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":"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":11066,"output_tokens":2842,"usd":0.037914},"stage2":{"model":"claude-opus-4-6","input_tokens":6213,"output_tokens":2949,"usd":0.157185},"total_usd":0.195099,"stage1_batch_id":"msgbatch_011kfMfE81o6CTcyhVUqumuW","stage2_batch_id":"msgbatch_01DTputS6WNkH745x1nVSoBo","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2012,\n      \"finding\": \"CHMP4C, a human ESCRT-III subunit, functions in the Aurora B-dependent abscission checkpoint to prevent premature cytokinetic abscission. CHMP4C engages the chromosomal passenger complex (CPC) via direct interaction with Borealin, and is phosphorylated by Aurora B, which inhibits abscission. CHMP4C shows differential spatiotemporal distribution during late cytokinesis consistent with this regulatory role.\",\n      \"method\": \"Co-immunoprecipitation (CHMP4C–Borealin interaction), phosphorylation assays, RNAi depletion with cytokinesis/DNA damage phenotypic readouts, live-cell imaging\",\n      \"journal\": \"Science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal Co-IP plus functional epistasis, high citation count, replicated by 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 CHMP4C membrane association, while Aurora B phosphorylation interferes with its membrane-remodelling activity without blocking spiral filament assembly at the abscission site. Two spatially distinct pools of phosphorylated CHMP4C exist during cytokinesis. The centralspindlin complex associates preferentially with unphosphorylated CHMP4C, suggesting a relay mechanism in which gradual dephosphorylation of CHMP4C transfers control from CPC to centralspindlin to trigger abscission.\",\n      \"method\": \"Atomic force microscopy (membrane binding/remodelling in vitro), co-immunoprecipitation (CHMP4C interactome in telophase), phospho-mutant analysis, fluorescence microscopy\",\n      \"journal\": \"Open Biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — in vitro reconstitution of membrane remodelling combined with interactome Co-IP and phospho-mutant epistasis\",\n      \"pmids\": [\"27784789\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"CHMP4C localizes to kinetochores in prometaphase and promotes localisation of the RZZ (Rod-ZW10-Zwilch) complex and Mad1-Mad2 checkpoint proteins to unattached kinetochores. CHMP4C binds directly to ZW10 through a small C-terminal region. Loss of CHMP4C impairs mitotic checkpoint arrest and causes chromosome misalignment/missegregation. Constitutive kinetochore targeting of CHMP4C causes a ZW10-dependent metaphase arrest. These functions do not require ESCRT-dependent membrane remodelling.\",\n      \"method\": \"RNAi depletion with mitotic checkpoint assays (nocodazole arrest), co-immunoprecipitation (CHMP4C–ZW10), live-cell imaging, constitutive kinetochore-tethering constructs\",\n      \"journal\": \"Journal of Cell Biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal Co-IP plus epistasis with ZW10-dependent checkpoint arrest, multiple orthogonal methods\",\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 Hec1-Nuf2 kinetochore localisation in prometaphase. Nuf2 is required for CHMP4C kinetochore targeting. CHMP4C binds tubulin in cell extracts and directly binds and bundles microtubules in vitro through its highly basic N-terminal region (amino acids 1–77). The 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 assays, N-terminal deletion mutants, kinetochore-tethering rescue experiments\",\n      \"journal\": \"Chromosoma\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — in vitro microtubule binding assay plus Co-IP and domain-mapping mutagenesis\",\n      \"pmids\": [\"29968190\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"CHMP4C enables midbody remnant (MBR) inheritance by maintaining the integrity of a membranous stalk connecting the MBR to the apical plasma membrane of epithelial cells. Depletion of CHMP4C dramatically reduces the percentage of ciliated cells, linking MBR inheritance to primary cilium formation.\",\n      \"method\": \"Correlative light and ultra-high-resolution scanning electron microscopy, siRNA depletion with ciliation readout\",\n      \"journal\": \"iScience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct localization by high-resolution EM plus functional consequence (loss of ciliation), single study\",\n      \"pmids\": [\"32629610\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"CHMP4C (but not paralogues CHMP4A or CHMP4B) is specifically required for integrity of the recycling endosomal network; its depletion causes extensive tubulation of transferrin receptor-positive recycling endosomes indicative of aberrant fission. Exogenous CHMP4C localises to recycling endosomes. This role in recycling endosome fission is distinct from its late-endocytic pathway function.\",\n      \"method\": \"siRNA depletion screen, ultrastructural electron microscopy, confocal microscopy (transferrin receptor co-localisation), virus production as biological readout\",\n      \"journal\": \"mBio\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct localization to recycling endosomes with ultrastructural functional phenotype, single study with multiple methods\",\n      \"pmids\": [\"33975940\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Aurora B phosphorylates CHMP4C in response to ionising radiation in non-small cell lung cancer cells, maintaining cell cycle checkpoint and cellular viability; CHMP4C depletion enhances radiosensitivity, delays S-phase, and reduces IR-induced γH2AX foci formation in a p53-independent manner.\",\n      \"method\": \"Western blotting (phosphorylation), siRNA depletion, flow cytometry (cell cycle), colony formation assay, γH2AX/53BP1 foci immunofluorescence\",\n      \"journal\": \"International Journal of Molecular Sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — phosphorylation assay plus functional KD phenotypes, single lab, multiple orthogonal readouts\",\n      \"pmids\": [\"26712741\"],\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; CHMP4C knockout exacerbates pressure-overload-induced cardiac hypertrophy, while cardiomyocyte-specific overexpression attenuates it. The EGFR inhibitor canertinib counteracts the hypertrophy exacerbation caused by CHMP4C knockdown, confirming EGFR dependence.\",\n      \"method\": \"Co-immunoprecipitation (CHMP4C–EGFR), confocal fluorescent co-localisation, CHMP4C knockout and cardiac-specific overexpression mouse models, EGFR inhibitor rescue\",\n      \"journal\": \"Hypertension\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — Co-IP plus in vivo genetic models with pharmacological rescue, single study\",\n      \"pmids\": [\"37846580\"],\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, which inhibits RIPK1/RIPK3/MLKL pathway phosphorylation and suppresses necroptosis in pancreatic cancer cells. CHMP4C also promotes exocytic secretion of phospho-MLKL via extracellular vesicles to further suppress necroptosis.\",\n      \"method\": \"RNA immunoprecipitation, MeRIP-qPCR (m5C methylation), co-immunoprecipitation (CHMP4C–YBX1), in vitro and in vivo functional assays, extracellular vesicle isolation\",\n      \"journal\": \"Journal of Advanced Research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple biochemical methods (RIP, MeRIP, Co-IP) in a single study with in vivo validation\",\n      \"pmids\": [\"39870301\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"CHMP4C deficiency in endothelial cells impairs endocytic trafficking of GSK3β, leading to GSK3β hyperactivation and repression of the Wnt/β-catenin pathway, causing G1/S arrest and impaired angiogenesis. Selective GSK3β inhibition rescues these defects.\",\n      \"method\": \"siRNA knockdown, RNA-Seq, electron microscopy and immunohistochemical co-localisation (GSK3β endocytic trafficking), CHMP4C knockout mouse hind-limb ischemia model, GSK3β inhibitor rescue\",\n      \"journal\": \"FASEB Journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct ultrastructural evidence of trafficking defect plus in vivo KO and pharmacological rescue, single study\",\n      \"pmids\": [\"41195682\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"CHMP4C is an ESCRT-III subunit that is phosphorylated by Aurora B and functions as a checkpoint factor during cytokinetic abscission (via Borealin/CPC interaction and centralspindlin relay), promotes mitotic spindle checkpoint signaling by recruiting the RZZ complex to kinetochores through ZW10 binding, stabilizes kinetochore-microtubule attachments by associating with NDC80 components and directly bundling microtubules via its N-terminal domain, regulates midbody remnant inheritance and primary ciliogenesis, mediates fission of recycling endosomes, and in non-mitotic contexts promotes lysosomal degradation of membrane receptors such as EGFR and modulates endocytic trafficking of GSK3β to control Wnt/β-catenin signaling.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"CHMP4C is an ESCRT-III subunit with multifaceted roles in cytokinesis, mitotic checkpoint signaling, endosomal membrane remodeling, and receptor trafficking. During cytokinesis, CHMP4C binds Borealin to engage the chromosomal passenger complex and is phosphorylated by Aurora B, which inhibits its membrane-remodeling activity and prevents premature abscission; dephosphorylation transfers control to centralspindlin, triggering abscission completion [PMID:22422861, PMID:27784789]. Independent of its ESCRT membrane-remodeling function, CHMP4C localizes to kinetochores via the NDC80 complex, recruits the RZZ checkpoint complex through direct ZW10 binding to sustain spindle assembly checkpoint signaling, and bundles microtubules through its basic N-terminal domain to stabilize kinetochore-microtubule attachments [PMID:29362225, PMID:29968190]. Beyond mitosis, CHMP4C mediates fission of recycling endosomes, promotes lysosomal degradation of activated EGFR, regulates endocytic trafficking of GSK3β to modulate Wnt/β-catenin signaling, and supports midbody remnant inheritance required for primary ciliogenesis [PMID:33975940, PMID:37846580, PMID:41195682, PMID:32629610].\",\n  \"teleology\": [\n    {\n      \"year\": 2012,\n      \"claim\": \"Establishing that CHMP4C functions as a checkpoint factor in cytokinetic abscission resolved how cells delay membrane scission when chromatin bridges persist: CHMP4C directly engages Borealin/CPC and is phosphorylated by Aurora B to inhibit abscission.\",\n      \"evidence\": \"Reciprocal co-immunoprecipitation of CHMP4C–Borealin, phosphorylation assays, RNAi with cytokinesis phenotypic readouts in human cells\",\n      \"pmids\": [\"22422861\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"How CHMP4C phosphorylation mechanistically blocks membrane scission was not resolved\",\n        \"The downstream relay from CPC to abscission effectors was unclear\"\n      ]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Demonstrating Aurora B-dependent CHMP4C phosphorylation after ionizing radiation extended its checkpoint role beyond cytokinesis, linking CHMP4C to DNA damage-induced cell cycle regulation and radiosensitivity in cancer cells.\",\n      \"evidence\": \"Western blotting for phospho-CHMP4C, siRNA depletion with flow cytometry and γH2AX foci quantification in NSCLC cells\",\n      \"pmids\": [\"26712741\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Mechanism by which CHMP4C influences γH2AX foci formation is unknown\",\n        \"Whether this reflects a direct DNA repair role or an indirect checkpoint effect was not distinguished\",\n        \"Single-lab finding, not independently replicated\"\n      ]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Reconstituting CHMP4C membrane binding and remodeling in vitro, and showing that Borealin blocks membrane association while Aurora B phosphorylation inhibits remodeling activity, provided a biochemical mechanism for abscission delay and identified centralspindlin as the relay partner for triggering abscission upon CHMP4C dephosphorylation.\",\n      \"evidence\": \"Atomic force microscopy on supported lipid bilayers, co-immunoprecipitation of CHMP4C interactome in telophase, phospho-mutant analysis\",\n      \"pmids\": [\"27784789\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"The phosphatase responsible for CHMP4C dephosphorylation was not identified\",\n        \"Whether the two spatially distinct phospho-CHMP4C pools have different functional outputs was not resolved\"\n      ]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Identifying CHMP4C as a kinetochore-localized promoter of spindle assembly checkpoint signaling — via direct ZW10 binding and recruitment of the RZZ/Mad1-Mad2 module — revealed a mitotic function independent of its canonical ESCRT membrane role, and its N-terminal microtubule-bundling activity explained how it stabilizes kinetochore-microtubule attachments.\",\n      \"evidence\": \"RNAi with mitotic checkpoint assays, co-immunoprecipitation of CHMP4C–ZW10 and CHMP4C–Hec1/Nuf2, in vitro microtubule binding/bundling, constitutive kinetochore-tethering constructs\",\n      \"pmids\": [\"29362225\", \"29968190\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"How CHMP4C is regulated at kinetochores (e.g., whether Aurora B phosphorylation modulates its kinetochore functions) is unknown\",\n        \"Structural basis for CHMP4C–ZW10 interaction was not determined\",\n        \"Whether the kinetochore and cytokinesis pools of CHMP4C are sequentially regulated in mitosis remains unclear\"\n      ]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Linking CHMP4C to midbody remnant inheritance and primary ciliogenesis showed that its abscission-related membrane function has downstream consequences for organelle biogenesis in epithelial cells.\",\n      \"evidence\": \"Correlative light and ultra-high-resolution scanning electron microscopy, siRNA depletion with ciliation readout\",\n      \"pmids\": [\"32629610\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"The specific membrane topology CHMP4C maintains at the midbody stalk is not defined\",\n        \"Whether this ciliogenesis defect is solely due to MBR loss or involves additional CHMP4C functions was not tested\",\n        \"Single study without independent replication\"\n      ]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Demonstrating that CHMP4C — uniquely among CHMP4 paralogues — is required for recycling endosome fission established a non-mitotic, paralogue-specific membrane scission role in the endosomal system.\",\n      \"evidence\": \"siRNA depletion screen, ultrastructural EM of tubulated recycling endosomes, confocal co-localization with transferrin receptor\",\n      \"pmids\": [\"33975940\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"How CHMP4C is specifically recruited to recycling endosomes is unknown\",\n        \"Whether VPS4 is required for this fission event was not tested\",\n        \"Single study; independent confirmation is lacking\"\n      ]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Showing that CHMP4C directly interacts with EGFR and promotes its lysosomal degradation provided a molecular link between ESCRT-III sorting and receptor downregulation, with in vivo relevance demonstrated by exacerbated cardiac hypertrophy in CHMP4C knockout mice rescued by EGFR inhibition.\",\n      \"evidence\": \"Co-immunoprecipitation of CHMP4C–EGFR, cardiac-specific overexpression and global knockout mouse models, EGFR inhibitor rescue\",\n      \"pmids\": [\"37846580\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Whether CHMP4C sorts other RTKs beyond EGFR is unknown\",\n        \"The mechanism distinguishing CHMP4C from other ESCRT-III subunits in EGFR degradation is not defined\",\n        \"Single study\"\n      ]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Two studies expanded CHMP4C's non-mitotic repertoire: one showed CHMP4C regulates endocytic trafficking of GSK3β to control Wnt/β-catenin signaling and angiogenesis, and another revealed CHMP4C–YBX1-mediated m5C modification of caspase-8 mRNA to suppress necroptosis, with additional exocytic secretion of phospho-MLKL via extracellular vesicles.\",\n      \"evidence\": \"siRNA/KO with RNA-Seq and EM-based trafficking analysis plus GSK3β inhibitor rescue in endothelial cells and hind-limb ischemia model; RIP, MeRIP-qPCR, Co-IP of CHMP4C–YBX1, and EV isolation in pancreatic cancer cells with in vivo validation\",\n      \"pmids\": [\"41195682\", \"39870301\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Whether CHMP4C's role in GSK3β trafficking involves its recycling endosome fission activity is not established\",\n        \"The CHMP4C–YBX1 interaction and m5C regulatory axis have not been independently replicated\",\n        \"How CHMP4C selectively packages phospho-MLKL into EVs is mechanistically undefined\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Major unresolved questions include how CHMP4C is differentially recruited to its distinct functional sites (kinetochores, midbody, recycling endosomes, late endosomes), what phosphatase reverses Aurora B phosphorylation to trigger abscission, whether CHMP4C's kinetochore and cytokinesis functions are coordinated during mitotic progression, and the structural basis for its paralogue-specific activities.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"No structural model of CHMP4C–ZW10 or CHMP4C–Borealin complexes exists\",\n        \"Identity of CHMP4C phosphatase unknown\",\n        \"Basis for paralogue specificity (CHMP4C vs. CHMP4A/B) at recycling endosomes not determined\"\n      ]\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, 3]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005694\", \"supporting_discovery_ids\": [2, 3]},\n      {\"term_id\": \"GO:0031410\", \"supporting_discovery_ids\": [5, 9]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [1]},\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [1, 4]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1640170\", \"supporting_discovery_ids\": [0, 1, 2, 3]},\n      {\"term_id\": \"R-HSA-5653656\", \"supporting_discovery_ids\": [5, 7, 9]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [7, 9]},\n      {\"term_id\": \"R-HSA-1852241\", \"supporting_discovery_ids\": [4]}\n    ],\n    \"complexes\": [\n      \"ESCRT-III\"\n    ],\n    \"partners\": [\n      \"BOREALIN\",\n      \"ZW10\",\n      \"HEC1\",\n      \"NUF2\",\n      \"EGFR\",\n      \"YBX1\",\n      \"GSK3B\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}