{"gene":"CHMP5","run_date":"2026-06-09T22:57:18","timeline":{"discoveries":[{"year":2006,"finding":"CHMP5 knockout in mice causes early embryonic lethality associated with enlarged late endosomal compartments containing abundant internal vesicles. CHMP5-deficient cells show reduced degradative capacity, accumulation of undigested proteins from multiple pathways in enlarged MVBs that fail to traffic cargo to lysosomes, and enhanced signal transduction due to impaired lysosomal degradation of activated receptors. CHMP5 thus regulates late endosome function downstream of MVB formation, distinct from classical ESCRT-III mutants in yeast.","method":"Conditional gene knockout in mice, transmission electron microscopy, endosomal fractionation, degradation assays, immunofluorescence","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — clean KO with defined cellular phenotype (EM, degradation assays, receptor signaling), replicated across multiple assays in a focused mechanistic study","pmids":["16567502"],"is_preprint":false},{"year":2005,"finding":"CHMP5 was identified as a LIP5-binding protein by co-immunoprecipitation and is primarily cytosolic. siRNA depletion of CHMP5 reduces EGFR degradation (similar to LIP5 depletion), implicating CHMP5 in MVB sorting. Unexpectedly, CHMP5 depletion increases release of infectious HIV-1 particles, whereas overexpression of C-terminally tagged CHMP5 disrupts the distribution of both early and late endocytic compartments.","method":"Co-immunoprecipitation, siRNA knockdown, EGFR degradation assay, HIV-1 budding assay, subcellular fractionation, immunofluorescence","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP identifies LIP5 as binding partner; multiple orthogonal functional assays (EGFR degradation, HIV budding, localization) in single lab","pmids":["15644320"],"is_preprint":false},{"year":2012,"finding":"The structure of yeast Vps60 (CHMP5 ortholog) fragment (residues 128–186) in complex with the N-terminal domain of Vta1 (LIP5 ortholog) was determined by NMR. Vps60(128-186) interacts with Vta1NTD through helices α4′ and α5′, extending over the MIT2 domain helices 1–3, representing a novel MIT-domain recognition mode. Vps60 binding does not induce conformational changes in Vta1, suggesting an indirect mechanism for Vps4 ATPase stimulation.","method":"NMR structure determination, in vitro binding assays","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — atomic-resolution NMR structure with functional validation of the interaction in a single focused study","pmids":["23105107"],"is_preprint":false},{"year":2015,"finding":"Crystal structure of human LIP5 N-terminal domain (LIP5NTD) in complex with MIM motifs of CHMP5 and CHMP1B was determined at 1 Å resolution. CHMP5 strongly inhibits LIP5-mediated stimulation of VPS4 ATPase activity. The structure reveals that CHMP5 binding induces a conformational change in LIP5NTD via insertion of conserved CHMP5 Tyr182 at the core of LIP5NTD; mutation of Tyr182 partially relieves CHMP5-mediated inhibition. This identifies CHMP5 as a negative allosteric switch controlling LIP5-mediated VPS4 stimulation in metazoans.","method":"X-ray crystallography (1 Å resolution), in vitro ATPase activity assay, site-directed mutagenesis, binding assays","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structure plus mutagenesis plus functional ATPase assay, all in one study with rigorous controls","pmids":["25637630"],"is_preprint":false},{"year":2012,"finding":"CHMP5 C-terminal tail (last 20 residues) binds Brox (mammalian paralog of Alix) and specifically recruits endogenous Brox to detergent-resistant membrane fractions. The CHMP5 C-terminal tail adopts a tandem β-hairpin structure (rather than the α-helix used by CHMP4B) to bind the same concave surface of Brox. An additional Brox:CHMP5 interface involves a unique CHMP5 hydrophobic pocket engaging Brox residue Y348, not conserved among other Bro1 domain proteins.","method":"X-ray crystallography, Co-immunoprecipitation, detergent-resistant membrane fractionation, NMR/structural analysis","journal":"Structure (London, England : 1993)","confidence":"High","confidence_rationale":"Tier 1 / Moderate — crystal/structural determination of CHMP5 C-terminal β-hairpin plus co-IP validation of Brox recruitment in cells","pmids":["22484091"],"is_preprint":false},{"year":2015,"finding":"Conditional deletion of CHMP5 in osteoclasts leads to increased bone resorption and exuberant bone formation resembling Paget's disease. CHMP5-deficient osteoclasts display increased RANKL-induced NF-κB activation and osteoclast differentiation. Biochemically, CHMP5 cooperates with VCP/p97 to stabilize IκBα by down-regulating IκBα ubiquitination via the deubiquitinating enzyme USP15, placing CHMP5 in a VCP/p97–CHMP5–USP15–IκBα axis downstream of RANK.","method":"Conditional knockout in osteoclasts, genetic epistasis (Rank haploinsufficiency rescue), antiresorptive treatment rescue, co-immunoprecipitation, ubiquitination assays, NF-κB reporter assays","journal":"The Journal of experimental medicine","confidence":"High","confidence_rationale":"Tier 2 / Strong — conditional KO with defined phenotype, genetic epistasis rescue, biochemical pathway placement (Co-IP, ubiquitination assay) across multiple orthogonal methods","pmids":["26195726"],"is_preprint":false},{"year":2017,"finding":"CHMP5 is essential for T cell development: conditional deletion in thymocyte precursors abolishes T cell development due to impaired post-selection survival. CHMP5 promotes stabilization of pro-survival protein Bcl-2, and the developmental block is rescued by genetic deletion of pro-apoptotic Bim or transgenic Bcl-2 expression. Mechanistically, TCR-mediated positive selection stabilizes CHMP5 protein by inducing its interaction with the deubiquitinase USP8, identifying a post-translational control axis.","method":"Conditional knockout, genetic epistasis (Bim KO and Bcl-2 transgene rescue), co-immunoprecipitation (CHMP5–USP8 interaction), flow cytometry, Western blot","journal":"Nature immunology","confidence":"High","confidence_rationale":"Tier 2 / Strong — conditional KO with clear phenotype, multiple genetic rescue experiments, and Co-IP identification of USP8 as stabilizing partner","pmids":["28553951"],"is_preprint":false},{"year":2023,"finding":"Vps60 (yeast ortholog of CHMP5) nucleates alternative ESCRT-III copolymers that recruit Vps2, Vps24, Did2, and Ist1 on membranes, independently of Snf7 (CHMP4). In fibroblasts, Vps60/CHMP5 and Snf7/CHMP4 both associate with endosomes and the cytokinetic midbody but are spatially segregated with different recruitment dynamics. Unlike Snf7/CHMP4, Vps60/CHMP5 is not recruited during nuclear envelope reformation, indicating functionally distinct ESCRT-III filament populations.","method":"In vitro membrane reconstitution, fluorescence microscopy (live imaging and FRAP), electron microscopy of filaments, genetic deletion of subunits","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — membrane reconstitution of filaments plus live-cell imaging localizing CHMP5 to distinct cellular sites with functional differentiation from CHMP4 pathway","pmids":["37768378"],"is_preprint":false},{"year":2003,"finding":"Mos10/Vps60 (yeast ortholog of CHMP5) is specifically required for filament maturation in S. cerevisiae pseudohyphal growth, a stage distinct from early filamentous growth. The mos10/mos10 phenotype is not recapitulated by mutants in other endocytosis or VPS genes, suggesting a specific cargo-targeting function of Vps60 under filament maturation conditions.","method":"Genetic screen, homozygous deletion mutant analysis, microscopy of pseudohyphal morphology","journal":"Molecular microbiology","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — genetic screen plus phenotypic characterization in yeast; function inferred from genetic specificity rather than direct biochemical assay","pmids":["12940986"],"is_preprint":false},{"year":2018,"finding":"CHMP5 mRNA and protein expression are directly down-regulated by miR-429 via its 3′UTR, as confirmed by luciferase reporter assay. CHMP5 is overexpressed in DSS-induced colitis mouse model and human ulcerative colitis tissues, and its down-regulation by miR-429 inhibits colon cancer cell growth and cell cycle progression.","method":"Luciferase reporter assay, Western blot, qRT-PCR, flow cytometry","journal":"Inflammation research","confidence":"Medium","confidence_rationale":"Tier 3 / Weak — luciferase reporter confirms miR-429 directly targets CHMP5 3′UTR; single lab, single method for the direct regulatory link","pmids":["30334065"],"is_preprint":false}],"current_model":"CHMP5 (also known as Vps60/Mos10) is an ESCRT-III family protein that nucleates alternative ESCRT-III filaments independent of CHMP4/Snf7, functions downstream of MVB formation to regulate late endosomal cargo trafficking to lysosomes, acts as a negative allosteric inhibitor of VPS4 ATPase by binding LIP5/Vta1 (blocking LIP5-mediated VPS4 stimulation via insertion of Tyr182 into LIP5NTD), recruits the Bro1-domain protein Brox to membranes via a C-terminal β-hairpin, dampens NF-κB signaling in osteoclasts by cooperating with VCP/p97 to stabilize IκBα through the deubiquitinase USP15, and supports post-selection thymocyte survival by stabilizing Bcl-2 through a TCR-induced interaction with the deubiquitinase USP8."},"narrative":{"mechanistic_narrative":"CHMP5 (Vps60/Mos10) is an ESCRT-III family protein that nucleates an alternative class of ESCRT-III copolymers and regulates late endosomal maturation and cargo trafficking to lysosomes [PMID:16567502, PMID:37768378]. Loss of CHMP5 produces enlarged multivesicular endosomes that fail to deliver cargo to lysosomes, reducing degradative capacity and enhancing receptor signaling, placing CHMP5 function downstream of MVB formation rather than at the canonical ESCRT-III step [PMID:16567502, PMID:15644320]. On membranes CHMP5/Vps60 seeds filaments that recruit Vps2, Vps24, Did2, and Ist1 independently of the CHMP4/Snf7 pathway, and CHMP5- and CHMP4-based filaments occupy spatially distinct sites with different dynamics, defining functionally separate ESCRT-III populations [PMID:37768378]. CHMP5 controls ESCRT disassembly machinery as a negative allosteric switch: it binds the VPS4 cofactor LIP5 (Vta1) through a MIM motif, and insertion of its conserved Tyr182 into the LIP5 N-terminal domain inhibits LIP5-mediated stimulation of VPS4 ATPase activity [PMID:23105107, PMID:25637630]. Through its C-terminal tail, which adopts a tandem β-hairpin fold, CHMP5 binds and recruits the Bro1-domain protein Brox to detergent-resistant membranes [PMID:22484091]. Beyond trafficking, CHMP5 serves tissue-specific signaling and survival roles: in osteoclasts it cooperates with VCP/p97 to stabilize IκBα via the deubiquitinase USP15, dampening RANKL-induced NF-κB activation, and its loss causes a Paget's-like bone phenotype [PMID:26195726]; in thymocytes, TCR-induced engagement of the deubiquitinase USP8 stabilizes CHMP5 protein, which promotes Bcl-2 stabilization to support post-selection T cell survival [PMID:28553951].","teleology":[{"year":2003,"claim":"Established that the yeast CHMP5 ortholog has a function distinct from generic endocytic/VPS machinery, hinting at a specialized cargo-targeting role rather than a redundant ESCRT step.","evidence":"Genetic screen and deletion mutant phenotyping in S. cerevisiae pseudohyphal growth","pmids":["12940986"],"confidence":"Medium","gaps":["Function inferred from genetic specificity, not direct biochemistry","No molecular partners or mechanism defined","Relevance to metazoan CHMP5 trafficking not established"]},{"year":2005,"claim":"Identified LIP5 as a direct CHMP5 binding partner and placed CHMP5 in MVB sorting, while flagging unexpected effects on HIV-1 budding and endocytic compartment organization.","evidence":"Co-immunoprecipitation, siRNA EGFR degradation and HIV-1 budding assays, subcellular fractionation in human cells","pmids":["15644320"],"confidence":"High","gaps":["Molecular basis of the LIP5 interaction unresolved","Mechanism of HIV budding effect not defined","Did not distinguish CHMP5 from classical ESCRT-III function"]},{"year":2006,"claim":"Defined the cellular consequence of CHMP5 loss in vivo, showing it acts downstream of MVB formation to enable cargo delivery to lysosomes, distinct from classical yeast ESCRT-III mutants.","evidence":"Conditional mouse knockout with TEM, endosomal fractionation, degradation and receptor signaling assays","pmids":["16567502"],"confidence":"High","gaps":["Did not resolve the biochemical step CHMP5 controls","Filament-level activity not addressed","Embryonic lethality limited tissue-level analysis"]},{"year":2012,"claim":"Provided the structural basis for two distinct CHMP5 protein interfaces — the Vta1/LIP5 recognition mode and the Brox-recruiting C-terminal β-hairpin — clarifying how CHMP5 engages disassembly and Bro1-domain machinery.","evidence":"NMR structure of Vps60(128-186):Vta1NTD and crystal/structural analysis of the CHMP5 C-terminal tail bound to Brox, with Co-IP and membrane fractionation","pmids":["23105107","22484091"],"confidence":"High","gaps":["Functional consequence of Vta1 binding (ATPase modulation) not yet defined in these studies","Cellular role of Brox recruitment not established","Whether interfaces act simultaneously unknown"]},{"year":2015,"claim":"Resolved how CHMP5 controls ESCRT disassembly, defining it as a negative allosteric switch that inhibits LIP5-driven VPS4 ATPase stimulation via Tyr182 insertion into LIP5NTD.","evidence":"1 Å crystal structure of LIP5NTD with CHMP5/CHMP1B MIM motifs, ATPase assays, and Tyr182 mutagenesis","pmids":["25637630"],"confidence":"High","gaps":["When and where this inhibition operates in vivo unclear","How inhibition is relieved during normal cycling not defined","Link to the enlarged-endosome phenotype not directly tested"]},{"year":2015,"claim":"Revealed a signaling role beyond trafficking, placing CHMP5 in a VCP/p97–CHMP5–USP15–IκBα axis that restrains RANKL-induced NF-κB activation in osteoclasts.","evidence":"Conditional osteoclast knockout with genetic epistasis rescue, Co-IP, ubiquitination and NF-κB reporter assays","pmids":["26195726"],"confidence":"High","gaps":["How ESCRT/trafficking activity connects to IκBα stabilization unresolved","Direct CHMP5–USP15 versus VCP-bridged interaction not fully dissected","Generality beyond osteoclasts unknown"]},{"year":2017,"claim":"Identified a post-translational control axis in which TCR signaling stabilizes CHMP5 via USP8, and CHMP5 in turn stabilizes Bcl-2 to enable post-selection thymocyte survival.","evidence":"Conditional thymocyte knockout with Bim-KO and Bcl-2-transgene rescue, Co-IP (CHMP5–USP8), flow cytometry and Western blot","pmids":["28553951"],"confidence":"High","gaps":["Mechanism linking CHMP5 to Bcl-2 stabilization not defined","Whether ESCRT activity is required for the survival role unknown","Direct versus indirect USP8 stabilization of CHMP5 not resolved"]},{"year":2023,"claim":"Demonstrated that CHMP5/Vps60 nucleates a Snf7/CHMP4-independent ESCRT-III filament population with distinct subunit composition, localization, and dynamics, explaining its non-redundant role.","evidence":"In vitro membrane reconstitution, live-cell imaging/FRAP, EM of filaments, and subunit deletions in yeast and fibroblasts","pmids":["37768378"],"confidence":"High","gaps":["Specific membrane-remodeling reaction served by CHMP5 filaments not defined","How CHMP5 and CHMP4 pathways are spatially segregated unknown","Cargo specificity of the alternative filament unresolved"]},{"year":2018,"claim":"Showed CHMP5 expression is directly repressed by miR-429 and is elevated in colitis and colon cancer contexts, linking its dosage to proliferation.","evidence":"Luciferase 3′UTR reporter, qRT-PCR/Western blot, and flow cytometry in colon cancer cells and colitis models","pmids":["30334065"],"confidence":"Medium","gaps":["Single-method evidence for the direct regulatory link","How CHMP5 level drives cell-cycle progression mechanistically not defined","Connection to ESCRT trafficking function not established"]},{"year":null,"claim":"How CHMP5's biochemical activities — alternative ESCRT-III filament nucleation and VPS4/LIP5 inhibition — are mechanistically coupled to its diverse signaling roles (NF-κB restraint, Bcl-2 stabilization) remains unresolved.","evidence":"","pmids":[],"confidence":"High","gaps":["No unified model linking membrane-remodeling activity to deubiquitinase-dependent protein stabilization","Whether trafficking and signaling roles share a common molecular step is untested","Tissue-specific partner selection not explained"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[2,3]},{"term_id":"GO:0005198","term_label":"structural molecule activity","supporting_discovery_ids":[7]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[4]}],"localization":[{"term_id":"GO:0005768","term_label":"endosome","supporting_discovery_ids":[0,1,7]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[1]},{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[4,7]}],"pathway":[{"term_id":"R-HSA-9609507","term_label":"Protein localization","supporting_discovery_ids":[0,1]},{"term_id":"R-HSA-5653656","term_label":"Vesicle-mediated transport","supporting_discovery_ids":[0,7]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[5,6]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[6]}],"complexes":["ESCRT-III"],"partners":["LIP5","VPS4","BROX","VCP","USP15","USP8"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q9NZZ3","full_name":"Charged multivesicular body protein 5","aliases":["Chromatin-modifying protein 5","SNF7 domain-containing protein 2","Vacuolar protein sorting-associated protein 60","Vps60","hVps60"],"length_aa":219,"mass_kda":24.6,"function":"Probable peripherally associated 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) (PubMed:14519844). 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 (PubMed:14519844)","subcellular_location":"Cytoplasm, cytosol; Endosome membrane; Midbody","url":"https://www.uniprot.org/uniprotkb/Q9NZZ3/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":true,"resolved_as":"","url":"https://depmap.org/portal/gene/CHMP5","classification":"Common Essential","n_dependent_lines":939,"n_total_lines":1208,"dependency_fraction":0.777317880794702},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"CLTA","stoichiometry":0.2},{"gene":"CLTB","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/CHMP5","total_profiled":1310},"omim":[{"mim_id":"610902","title":"VESSICLE TRAFFICKING 1; VTA1","url":"https://www.omim.org/entry/610902"},{"mim_id":"610900","title":"CHARGED MULTIVESICULAR BODY PROTEIN 5; CHMP5","url":"https://www.omim.org/entry/610900"},{"mim_id":"610897","title":"CHARGED MULTIVESICULAR BODY PROTEIN 4B; CHMP4B","url":"https://www.omim.org/entry/610897"},{"mim_id":"164010","title":"CHARGED MULTIVESICULAR BODY PROTEIN 1A; CHMP1A","url":"https://www.omim.org/entry/164010"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Microtubules","reliability":"Supported"},{"location":"Cytosol","reliability":"Supported"},{"location":"Midbody","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/CHMP5"},"hgnc":{"alias_symbol":["Spike","Vps60","CGI-34","HSPC177"],"prev_symbol":["C9orf83","SNF7DC2"]},"alphafold":{"accession":"Q9NZZ3","domains":[{"cath_id":"1.10.287","chopping":"16-104","consensus_level":"high","plddt":96.5173,"start":16,"end":104}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9NZZ3","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9NZZ3-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9NZZ3-F1-predicted_aligned_error_v6.png","plddt_mean":79.38},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=CHMP5","jax_strain_url":"https://www.jax.org/strain/search?query=CHMP5"},"sequence":{"accession":"Q9NZZ3","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9NZZ3.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9NZZ3/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9NZZ3"}},"corpus_meta":[{"pmid":"27578435","id":"PMC_27578435","title":"Structure, Function, and Evolution of Coronavirus Spike Proteins.","date":"2016","source":"Annual review of virology","url":"https://pubmed.ncbi.nlm.nih.gov/27578435","citation_count":1821,"is_preprint":false},{"pmid":"33106671","id":"PMC_33106671","title":"Spike mutation D614G alters SARS-CoV-2 fitness.","date":"2020","source":"Nature","url":"https://pubmed.ncbi.nlm.nih.gov/33106671","citation_count":1219,"is_preprint":false},{"pmid":"22816037","id":"PMC_22816037","title":"Mechanisms of coronavirus cell entry mediated by the viral spike protein.","date":"2012","source":"Viruses","url":"https://pubmed.ncbi.nlm.nih.gov/22816037","citation_count":921,"is_preprint":false},{"pmid":"33243994","id":"PMC_33243994","title":"SARS-CoV-2 spike-protein D614G mutation increases virion spike density and infectivity.","date":"2020","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/33243994","citation_count":764,"is_preprint":false},{"pmid":"21816910","id":"PMC_21816910","title":"Synthetic spike-in standards for RNA-seq experiments.","date":"2011","source":"Genome research","url":"https://pubmed.ncbi.nlm.nih.gov/21816910","citation_count":486,"is_preprint":false},{"pmid":"33154106","id":"PMC_33154106","title":"An ultrapotent synthetic nanobody neutralizes SARS-CoV-2 by stabilizing inactive Spike.","date":"2020","source":"Science (New York, N.Y.)","url":"https://pubmed.ncbi.nlm.nih.gov/33154106","citation_count":335,"is_preprint":false},{"pmid":"27712627","id":"PMC_27712627","title":"Coronavirus Spike Protein and Tropism Changes.","date":"2016","source":"Advances in virus research","url":"https://pubmed.ncbi.nlm.nih.gov/27712627","citation_count":328,"is_preprint":false},{"pmid":"22590686","id":"PMC_22590686","title":"Ready, set, fuse! 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transmission.","date":"2021","source":"Science China. Life sciences","url":"https://pubmed.ncbi.nlm.nih.gov/33587268","citation_count":11,"is_preprint":false},{"pmid":"12940986","id":"PMC_12940986","title":"Mos10 (Vps60) is required for normal filament maturation in Saccharomyces cerevisiae.","date":"2003","source":"Molecular microbiology","url":"https://pubmed.ncbi.nlm.nih.gov/12940986","citation_count":11,"is_preprint":false},{"pmid":"35228064","id":"PMC_35228064","title":"There is nothing exempt from the peril of mutation - The Omicron spike.","date":"2022","source":"Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie","url":"https://pubmed.ncbi.nlm.nih.gov/35228064","citation_count":11,"is_preprint":false},{"pmid":"39657663","id":"PMC_39657663","title":"A glucocorticoid spike derails muscle repair to heterotopic ossification after spinal cord injury.","date":"2024","source":"Cell reports. Medicine","url":"https://pubmed.ncbi.nlm.nih.gov/39657663","citation_count":10,"is_preprint":false},{"pmid":"37676001","id":"PMC_37676001","title":"Characterization of CCoV-HuPn-2018 spike protein-mediated viral entry.","date":"2023","source":"Journal of virology","url":"https://pubmed.ncbi.nlm.nih.gov/37676001","citation_count":10,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":43018,"output_tokens":3452,"usd":0.090417,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":10586,"output_tokens":3884,"usd":0.075015,"stage2_stop_reason":"end_turn"},"total_usd":0.165432,"stage1_batch_id":"msgbatch_01ACAxJQabDsht39JXeWG22d","stage2_batch_id":"msgbatch_01QEU22A9U5sbPTgsMzTmvSf","note":"batch pricing = 50% of standard"},"stage1_raw":"Looking through the corpus, I need to identify papers about the human CHMP5 gene (also known as Vps60, CGI-34, HSPC177, C9orf83, SNF7DC2) and extract mechanistic findings.\n\nRelevant papers:\n- PMID:16567502 (CHMP5 in mouse embryogenesis, late endosome function)\n- PMID:15644320 (LIP5 and CHMP5 in MVB formation and HIV-1 budding)\n- PMID:26195726 (CHMP5 in bone turnover, NF-κB signaling)\n- PMID:28553951 (CHMP5 in T cell development)\n- PMID:23105107 (Vps60/CHMP5 structure with Vta1)\n- PMID:25637630 (CHMP5 regulation of VPS4 via LIP5)\n- PMID:22484091 (CHMP5 C-terminal tail interaction with Brox)\n- PMID:37768378 (Vps60/CHMP5 initiates alternative ESCRT-III filaments)\n- PMID:12940986 (Mos10/Vps60 in yeast filament maturation)\n- PMID:30334065 (MIR429 regulates CHMP5 expression)\n\n```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2006,\n      \"finding\": \"CHMP5 knockout in mice causes early embryonic lethality associated with enlarged late endosomal compartments containing abundant internal vesicles. CHMP5-deficient cells show reduced degradative capacity, accumulation of undigested proteins from multiple pathways in enlarged MVBs that fail to traffic cargo to lysosomes, and enhanced signal transduction due to impaired lysosomal degradation of activated receptors. CHMP5 thus regulates late endosome function downstream of MVB formation, distinct from classical ESCRT-III mutants in yeast.\",\n      \"method\": \"Conditional gene knockout in mice, transmission electron microscopy, endosomal fractionation, degradation assays, immunofluorescence\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — clean KO with defined cellular phenotype (EM, degradation assays, receptor signaling), replicated across multiple assays in a focused mechanistic study\",\n      \"pmids\": [\"16567502\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"CHMP5 was identified as a LIP5-binding protein by co-immunoprecipitation and is primarily cytosolic. siRNA depletion of CHMP5 reduces EGFR degradation (similar to LIP5 depletion), implicating CHMP5 in MVB sorting. Unexpectedly, CHMP5 depletion increases release of infectious HIV-1 particles, whereas overexpression of C-terminally tagged CHMP5 disrupts the distribution of both early and late endocytic compartments.\",\n      \"method\": \"Co-immunoprecipitation, siRNA knockdown, EGFR degradation assay, HIV-1 budding assay, subcellular fractionation, immunofluorescence\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP identifies LIP5 as binding partner; multiple orthogonal functional assays (EGFR degradation, HIV budding, localization) in single lab\",\n      \"pmids\": [\"15644320\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"The structure of yeast Vps60 (CHMP5 ortholog) fragment (residues 128–186) in complex with the N-terminal domain of Vta1 (LIP5 ortholog) was determined by NMR. Vps60(128-186) interacts with Vta1NTD through helices α4′ and α5′, extending over the MIT2 domain helices 1–3, representing a novel MIT-domain recognition mode. Vps60 binding does not induce conformational changes in Vta1, suggesting an indirect mechanism for Vps4 ATPase stimulation.\",\n      \"method\": \"NMR structure determination, in vitro binding assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — atomic-resolution NMR structure with functional validation of the interaction in a single focused study\",\n      \"pmids\": [\"23105107\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Crystal structure of human LIP5 N-terminal domain (LIP5NTD) in complex with MIM motifs of CHMP5 and CHMP1B was determined at 1 Å resolution. CHMP5 strongly inhibits LIP5-mediated stimulation of VPS4 ATPase activity. The structure reveals that CHMP5 binding induces a conformational change in LIP5NTD via insertion of conserved CHMP5 Tyr182 at the core of LIP5NTD; mutation of Tyr182 partially relieves CHMP5-mediated inhibition. This identifies CHMP5 as a negative allosteric switch controlling LIP5-mediated VPS4 stimulation in metazoans.\",\n      \"method\": \"X-ray crystallography (1 Å resolution), in vitro ATPase activity assay, site-directed mutagenesis, binding assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structure plus mutagenesis plus functional ATPase assay, all in one study with rigorous controls\",\n      \"pmids\": [\"25637630\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"CHMP5 C-terminal tail (last 20 residues) binds Brox (mammalian paralog of Alix) and specifically recruits endogenous Brox to detergent-resistant membrane fractions. The CHMP5 C-terminal tail adopts a tandem β-hairpin structure (rather than the α-helix used by CHMP4B) to bind the same concave surface of Brox. An additional Brox:CHMP5 interface involves a unique CHMP5 hydrophobic pocket engaging Brox residue Y348, not conserved among other Bro1 domain proteins.\",\n      \"method\": \"X-ray crystallography, Co-immunoprecipitation, detergent-resistant membrane fractionation, NMR/structural analysis\",\n      \"journal\": \"Structure (London, England : 1993)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — crystal/structural determination of CHMP5 C-terminal β-hairpin plus co-IP validation of Brox recruitment in cells\",\n      \"pmids\": [\"22484091\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Conditional deletion of CHMP5 in osteoclasts leads to increased bone resorption and exuberant bone formation resembling Paget's disease. CHMP5-deficient osteoclasts display increased RANKL-induced NF-κB activation and osteoclast differentiation. Biochemically, CHMP5 cooperates with VCP/p97 to stabilize IκBα by down-regulating IκBα ubiquitination via the deubiquitinating enzyme USP15, placing CHMP5 in a VCP/p97–CHMP5–USP15–IκBα axis downstream of RANK.\",\n      \"method\": \"Conditional knockout in osteoclasts, genetic epistasis (Rank haploinsufficiency rescue), antiresorptive treatment rescue, co-immunoprecipitation, ubiquitination assays, NF-κB reporter assays\",\n      \"journal\": \"The Journal of experimental medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — conditional KO with defined phenotype, genetic epistasis rescue, biochemical pathway placement (Co-IP, ubiquitination assay) across multiple orthogonal methods\",\n      \"pmids\": [\"26195726\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"CHMP5 is essential for T cell development: conditional deletion in thymocyte precursors abolishes T cell development due to impaired post-selection survival. CHMP5 promotes stabilization of pro-survival protein Bcl-2, and the developmental block is rescued by genetic deletion of pro-apoptotic Bim or transgenic Bcl-2 expression. Mechanistically, TCR-mediated positive selection stabilizes CHMP5 protein by inducing its interaction with the deubiquitinase USP8, identifying a post-translational control axis.\",\n      \"method\": \"Conditional knockout, genetic epistasis (Bim KO and Bcl-2 transgene rescue), co-immunoprecipitation (CHMP5–USP8 interaction), flow cytometry, Western blot\",\n      \"journal\": \"Nature immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — conditional KO with clear phenotype, multiple genetic rescue experiments, and Co-IP identification of USP8 as stabilizing partner\",\n      \"pmids\": [\"28553951\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Vps60 (yeast ortholog of CHMP5) nucleates alternative ESCRT-III copolymers that recruit Vps2, Vps24, Did2, and Ist1 on membranes, independently of Snf7 (CHMP4). In fibroblasts, Vps60/CHMP5 and Snf7/CHMP4 both associate with endosomes and the cytokinetic midbody but are spatially segregated with different recruitment dynamics. Unlike Snf7/CHMP4, Vps60/CHMP5 is not recruited during nuclear envelope reformation, indicating functionally distinct ESCRT-III filament populations.\",\n      \"method\": \"In vitro membrane reconstitution, fluorescence microscopy (live imaging and FRAP), electron microscopy of filaments, genetic deletion of subunits\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — membrane reconstitution of filaments plus live-cell imaging localizing CHMP5 to distinct cellular sites with functional differentiation from CHMP4 pathway\",\n      \"pmids\": [\"37768378\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"Mos10/Vps60 (yeast ortholog of CHMP5) is specifically required for filament maturation in S. cerevisiae pseudohyphal growth, a stage distinct from early filamentous growth. The mos10/mos10 phenotype is not recapitulated by mutants in other endocytosis or VPS genes, suggesting a specific cargo-targeting function of Vps60 under filament maturation conditions.\",\n      \"method\": \"Genetic screen, homozygous deletion mutant analysis, microscopy of pseudohyphal morphology\",\n      \"journal\": \"Molecular microbiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — genetic screen plus phenotypic characterization in yeast; function inferred from genetic specificity rather than direct biochemical assay\",\n      \"pmids\": [\"12940986\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"CHMP5 mRNA and protein expression are directly down-regulated by miR-429 via its 3′UTR, as confirmed by luciferase reporter assay. CHMP5 is overexpressed in DSS-induced colitis mouse model and human ulcerative colitis tissues, and its down-regulation by miR-429 inhibits colon cancer cell growth and cell cycle progression.\",\n      \"method\": \"Luciferase reporter assay, Western blot, qRT-PCR, flow cytometry\",\n      \"journal\": \"Inflammation research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Weak — luciferase reporter confirms miR-429 directly targets CHMP5 3′UTR; single lab, single method for the direct regulatory link\",\n      \"pmids\": [\"30334065\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"CHMP5 (also known as Vps60/Mos10) is an ESCRT-III family protein that nucleates alternative ESCRT-III filaments independent of CHMP4/Snf7, functions downstream of MVB formation to regulate late endosomal cargo trafficking to lysosomes, acts as a negative allosteric inhibitor of VPS4 ATPase by binding LIP5/Vta1 (blocking LIP5-mediated VPS4 stimulation via insertion of Tyr182 into LIP5NTD), recruits the Bro1-domain protein Brox to membranes via a C-terminal β-hairpin, dampens NF-κB signaling in osteoclasts by cooperating with VCP/p97 to stabilize IκBα through the deubiquitinase USP15, and supports post-selection thymocyte survival by stabilizing Bcl-2 through a TCR-induced interaction with the deubiquitinase USP8.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"CHMP5 (Vps60/Mos10) is an ESCRT-III family protein that nucleates an alternative class of ESCRT-III copolymers and regulates late endosomal maturation and cargo trafficking to lysosomes [#0, #7]. Loss of CHMP5 produces enlarged multivesicular endosomes that fail to deliver cargo to lysosomes, reducing degradative capacity and enhancing receptor signaling, placing CHMP5 function downstream of MVB formation rather than at the canonical ESCRT-III step [#0, #1]. On membranes CHMP5/Vps60 seeds filaments that recruit Vps2, Vps24, Did2, and Ist1 independently of the CHMP4/Snf7 pathway, and CHMP5- and CHMP4-based filaments occupy spatially distinct sites with different dynamics, defining functionally separate ESCRT-III populations [#7]. CHMP5 controls ESCRT disassembly machinery as a negative allosteric switch: it binds the VPS4 cofactor LIP5 (Vta1) through a MIM motif, and insertion of its conserved Tyr182 into the LIP5 N-terminal domain inhibits LIP5-mediated stimulation of VPS4 ATPase activity [#2, #3]. Through its C-terminal tail, which adopts a tandem β-hairpin fold, CHMP5 binds and recruits the Bro1-domain protein Brox to detergent-resistant membranes [#4]. Beyond trafficking, CHMP5 serves tissue-specific signaling and survival roles: in osteoclasts it cooperates with VCP/p97 to stabilize IκBα via the deubiquitinase USP15, dampening RANKL-induced NF-κB activation, and its loss causes a Paget's-like bone phenotype [#5]; in thymocytes, TCR-induced engagement of the deubiquitinase USP8 stabilizes CHMP5 protein, which promotes Bcl-2 stabilization to support post-selection T cell survival [#6].\",\n  \"teleology\": [\n    {\n      \"year\": 2003,\n      \"claim\": \"Established that the yeast CHMP5 ortholog has a function distinct from generic endocytic/VPS machinery, hinting at a specialized cargo-targeting role rather than a redundant ESCRT step.\",\n      \"evidence\": \"Genetic screen and deletion mutant phenotyping in S. cerevisiae pseudohyphal growth\",\n      \"pmids\": [\"12940986\"],\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Function inferred from genetic specificity, not direct biochemistry\", \"No molecular partners or mechanism defined\", \"Relevance to metazoan CHMP5 trafficking not established\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Identified LIP5 as a direct CHMP5 binding partner and placed CHMP5 in MVB sorting, while flagging unexpected effects on HIV-1 budding and endocytic compartment organization.\",\n      \"evidence\": \"Co-immunoprecipitation, siRNA EGFR degradation and HIV-1 budding assays, subcellular fractionation in human cells\",\n      \"pmids\": [\"15644320\"],\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Molecular basis of the LIP5 interaction unresolved\", \"Mechanism of HIV budding effect not defined\", \"Did not distinguish CHMP5 from classical ESCRT-III function\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Defined the cellular consequence of CHMP5 loss in vivo, showing it acts downstream of MVB formation to enable cargo delivery to lysosomes, distinct from classical yeast ESCRT-III mutants.\",\n      \"evidence\": \"Conditional mouse knockout with TEM, endosomal fractionation, degradation and receptor signaling assays\",\n      \"pmids\": [\"16567502\"],\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Did not resolve the biochemical step CHMP5 controls\", \"Filament-level activity not addressed\", \"Embryonic lethality limited tissue-level analysis\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Provided the structural basis for two distinct CHMP5 protein interfaces — the Vta1/LIP5 recognition mode and the Brox-recruiting C-terminal β-hairpin — clarifying how CHMP5 engages disassembly and Bro1-domain machinery.\",\n      \"evidence\": \"NMR structure of Vps60(128-186):Vta1NTD and crystal/structural analysis of the CHMP5 C-terminal tail bound to Brox, with Co-IP and membrane fractionation\",\n      \"pmids\": [\"23105107\", \"22484091\"],\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Functional consequence of Vta1 binding (ATPase modulation) not yet defined in these studies\", \"Cellular role of Brox recruitment not established\", \"Whether interfaces act simultaneously unknown\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Resolved how CHMP5 controls ESCRT disassembly, defining it as a negative allosteric switch that inhibits LIP5-driven VPS4 ATPase stimulation via Tyr182 insertion into LIP5NTD.\",\n      \"evidence\": \"1 Å crystal structure of LIP5NTD with CHMP5/CHMP1B MIM motifs, ATPase assays, and Tyr182 mutagenesis\",\n      \"pmids\": [\"25637630\"],\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"When and where this inhibition operates in vivo unclear\", \"How inhibition is relieved during normal cycling not defined\", \"Link to the enlarged-endosome phenotype not directly tested\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Revealed a signaling role beyond trafficking, placing CHMP5 in a VCP/p97–CHMP5–USP15–IκBα axis that restrains RANKL-induced NF-κB activation in osteoclasts.\",\n      \"evidence\": \"Conditional osteoclast knockout with genetic epistasis rescue, Co-IP, ubiquitination and NF-κB reporter assays\",\n      \"pmids\": [\"26195726\"],\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"How ESCRT/trafficking activity connects to IκBα stabilization unresolved\", \"Direct CHMP5–USP15 versus VCP-bridged interaction not fully dissected\", \"Generality beyond osteoclasts unknown\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Identified a post-translational control axis in which TCR signaling stabilizes CHMP5 via USP8, and CHMP5 in turn stabilizes Bcl-2 to enable post-selection thymocyte survival.\",\n      \"evidence\": \"Conditional thymocyte knockout with Bim-KO and Bcl-2-transgene rescue, Co-IP (CHMP5–USP8), flow cytometry and Western blot\",\n      \"pmids\": [\"28553951\"],\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Mechanism linking CHMP5 to Bcl-2 stabilization not defined\", \"Whether ESCRT activity is required for the survival role unknown\", \"Direct versus indirect USP8 stabilization of CHMP5 not resolved\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Demonstrated that CHMP5/Vps60 nucleates a Snf7/CHMP4-independent ESCRT-III filament population with distinct subunit composition, localization, and dynamics, explaining its non-redundant role.\",\n      \"evidence\": \"In vitro membrane reconstitution, live-cell imaging/FRAP, EM of filaments, and subunit deletions in yeast and fibroblasts\",\n      \"pmids\": [\"37768378\"],\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Specific membrane-remodeling reaction served by CHMP5 filaments not defined\", \"How CHMP5 and CHMP4 pathways are spatially segregated unknown\", \"Cargo specificity of the alternative filament unresolved\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Showed CHMP5 expression is directly repressed by miR-429 and is elevated in colitis and colon cancer contexts, linking its dosage to proliferation.\",\n      \"evidence\": \"Luciferase 3′UTR reporter, qRT-PCR/Western blot, and flow cytometry in colon cancer cells and colitis models\",\n      \"pmids\": [\"30334065\"],\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Single-method evidence for the direct regulatory link\", \"How CHMP5 level drives cell-cycle progression mechanistically not defined\", \"Connection to ESCRT trafficking function not established\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How CHMP5's biochemical activities — alternative ESCRT-III filament nucleation and VPS4/LIP5 inhibition — are mechanistically coupled to its diverse signaling roles (NF-κB restraint, Bcl-2 stabilization) remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"No unified model linking membrane-remodeling activity to deubiquitinase-dependent protein stabilization\", \"Whether trafficking and signaling roles share a common molecular step is untested\", \"Tissue-specific partner selection not explained\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [2, 3]},\n      {\"term_id\": \"GO:0005198\", \"supporting_discovery_ids\": [7]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [4]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005768\", \"supporting_discovery_ids\": [0, 1, 7]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [1]},\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [4, 7]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-9609507\", \"supporting_discovery_ids\": [0, 1]},\n      {\"term_id\": \"R-HSA-5653656\", \"supporting_discovery_ids\": [0, 7]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [5, 6]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [6]}\n    ],\n    \"complexes\": [\"ESCRT-III\"],\n    \"partners\": [\"LIP5\", \"VPS4\", \"BROX\", \"VCP\", \"USP15\", \"USP8\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}