{"gene":"CCT7","run_date":"2026-06-09T22:57:17","timeline":{"discoveries":[{"year":2016,"finding":"CCT7 (chaperonin containing TCP-1 subunit eta) interacts directly with the thromboxane A2 receptor β-isoform (TPβ) and β2-adrenergic receptor (β2AR) through their third intracellular loops and C-termini, as demonstrated by yeast two-hybrid screening, co-immunoprecipitation, and in vitro pull-down assays. CCT7 depletion by siRNA reduced total and cell-surface expression of both receptors and caused their redistribution to juxtanuclear aggresomes, indicating CCT7/TRiC chaperonin complex is required for proper folding, maturation, and trafficking of nascent GPCRs. Trp334 in the TPβ C-terminus was identified as critical for CCT7 interaction and TPβ maturation.","method":"Yeast two-hybrid screening, co-immunoprecipitation, in vitro pull-down assay, siRNA knockdown, site-directed mutagenesis, cell-surface expression assays","journal":"Molecular biology of the cell","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — multiple orthogonal methods (Y2H, Co-IP, in vitro pulldown, mutagenesis, KD phenotype) in single rigorous study","pmids":["27708139"],"is_preprint":false},{"year":2019,"finding":"CCT7 interacts with the FAdV-4 capsid protein hexon, and is required for viral replication in leghorn male hepatocellular (LMH) cells. Ectopic overexpression of CCT7 enhanced hexon expression, while RNAi-mediated knockdown of CCT7 reduced hexon expression and suppressed FAdV-4 replication.","method":"Co-immunoprecipitation (interaction identification), ectopic overexpression, RNAi knockdown with viral replication assay","journal":"Viruses","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — Co-IP plus functional KD/OE with clear phenotypic readout, single lab, two complementary methods","pmids":["30691230"],"is_preprint":false},{"year":2024,"finding":"CCT7 interacts with canine parvovirus capsid protein VP2, with the interaction region mapped to amino acids 231–320 of VP2 by truncation mutant analysis. CCT7 stabilizes VP2 protein (demonstrated by cycloheximide chase), and knockdown of CCT7 by RNAi or HSF1A inhibitor reduced VP2 expression and CPV replication, while CCT7 overexpression increased VP2 levels.","method":"Yeast one-to-one assay, co-immunoprecipitation, laser confocal co-localization, VP2 truncation mutant mapping, cycloheximide chase, RNAi knockdown, overexpression","journal":"Frontiers in microbiology","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — multiple orthogonal methods (Co-IP, CHX chase, truncation mapping, KD/OE), single lab","pmids":["38384266"],"is_preprint":false},{"year":2025,"finding":"The apical domain of CCT7 inhibits tau aggregation in vitro. Kinetic analyses and negative-stain electron microscopy show that aggregation of tau in the presence of the CCT7 apical domain follows a fragmentation model, and coarse-grained molecular dynamics simulations indicate tau interacts with distinct regions of the CCT7 apical domain compared to CCT3, consistent with their different inhibition mechanisms.","method":"Kinetic aggregation assays, negative-stain electron microscopy, coarse-grained molecular dynamics simulations","journal":"Protein science","confidence":"Medium","confidence_rationale":"Tier 1–2 / Moderate — in vitro biochemical assays plus EM and simulation, single lab, multiple orthogonal methods","pmids":["40400346"],"is_preprint":false},{"year":2025,"finding":"CCT7 directly binds β-catenin and facilitates its nuclear translocation, thereby stabilizing pluripotency through Wnt/β-catenin signaling in embryonic stem cells. CCT7 deficiency disrupts telomere length homeostasis, triggers DNA damage response pathways, induces epigenetic reprogramming, activates repeat elements and 2-cell transcriptional programs, and facilitates transition to a 2-cell-like (totipotent) state.","method":"CCT7 knockout/knockdown in ESCs, co-immunoprecipitation (CCT7–β-catenin), nuclear translocation assay, telomere length measurement, RNA-seq/epigenetic assays","journal":"Stem cell reports","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — Co-IP for direct binding, KO functional phenotype with multiple readouts, single lab","pmids":["41455472"],"is_preprint":false},{"year":2026,"finding":"CCT7 interacts with TRAF6 and facilitates its ubiquitination and degradation, thereby suppressing autophagy (reduced LC3-II, Beclin-1; increased p62) and promoting fibroblast fibrosis. Knockdown of CCT7 in fibroblasts reduced α-SMA and COL-I expression, suppressed fibroblast migration, and enhanced autophagy; these effects were reversed by TRAF6 knockdown, placing CCT7 upstream of TRAF6 in this pathway. In vivo CCT7 knockdown improved joint range of motion and reduced fibrosis.","method":"Co-immunoprecipitation (CCT7–TRAF6), ubiquitination assay, siRNA knockdown of CCT7 and TRAF6, autophagy marker quantification, in vivo animal model","journal":"Journal of cellular and molecular medicine","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — Co-IP, ubiquitination assay, epistatic rescue (TRAF6 KD reversal), in vivo validation, single lab","pmids":["41947340"],"is_preprint":false},{"year":2020,"finding":"CCT7 knockdown by siRNA in endometrial cancer cell lines (Ishikawa and RL95-2) suppressed proliferation, promoted apoptosis, and reduced invasion, establishing a functional role for CCT7 in endometrial cancer cell behavior.","method":"siRNA knockdown, proliferation assay, apoptosis assay, invasion assay","journal":"Frontiers in oncology","confidence":"Low","confidence_rationale":"Tier 3 / Weak — KD with phenotypic readout but no pathway placement or binding partner identification; single lab, single study","pmids":["32983981"],"is_preprint":false}],"current_model":"CCT7 is the eta subunit of the TRiC/CCT chaperonin complex that directly binds and promotes folding/maturation of client proteins including GPCRs (via their intracellular loops and C-termini), viral capsid proteins (hexon, VP2), and β-catenin (facilitating nuclear translocation for Wnt signaling); its apical domain also inhibits tau aggregation through a fragmentation-based mechanism, and it regulates autophagy by binding TRAF6 and promoting its ubiquitination and degradation."},"narrative":{"mechanistic_narrative":"CCT7 is the eta subunit of the TRiC/CCT chaperonin complex and functions as a chaperone that directly binds nascent or aggregation-prone client proteins to promote their folding, maturation, and trafficking [PMID:27708139]. It is required for proper folding and cell-surface delivery of G protein-coupled receptors, interacting with the thromboxane A2 receptor β-isoform and the β2-adrenergic receptor through their third intracellular loops and C-termini; loss of CCT7 reduces receptor expression and redirects them to juxtanuclear aggresomes, and Trp334 in the TPβ C-terminus is critical for the interaction [PMID:27708139]. CCT7 stabilizes viral capsid proteins as folding clients, binding the FAdV-4 hexon and the canine parvovirus VP2 capsid protein to support their accumulation and viral replication [PMID:30691230, PMID:38384266]. Through direct binding it also stabilizes and drives nuclear translocation of β-catenin, sustaining Wnt/β-catenin signaling and pluripotency in embryonic stem cells [PMID:41455472]. Beyond classical chaperone clients, the isolated CCT7 apical domain inhibits tau aggregation in vitro via a fragmentation-based mechanism [PMID:40400346], and CCT7 suppresses autophagy and promotes fibroblast fibrosis by binding TRAF6 and facilitating its ubiquitination and degradation [PMID:41947340].","teleology":[{"year":2016,"claim":"Established CCT7 as a chaperone required for GPCR biogenesis, answering how nascent receptors achieve correct folding and trafficking to the cell surface.","evidence":"Yeast two-hybrid, Co-IP, in vitro pull-down, site-directed mutagenesis, and siRNA knockdown with cell-surface expression assays for TPβ and β2AR","pmids":["27708139"],"confidence":"High","gaps":["Whether folding requires the full TRiC/CCT complex or CCT7 alone is not resolved","No structural model of the CCT7–receptor interface","Generality across other GPCR families not tested"]},{"year":2019,"claim":"Extended CCT7 client repertoire to viral structural proteins, showing it supports adenoviral capsid protein expression and replication.","evidence":"Co-IP plus ectopic overexpression and RNAi knockdown with FAdV-4 replication readout in LMH cells","pmids":["30691230"],"confidence":"Medium","gaps":["Direct folding/chaperone activity on hexon not demonstrated biochemically","Interaction interface on hexon not mapped","Single cell system"]},{"year":2024,"claim":"Demonstrated CCT7 stabilizes a second viral capsid protein, defining a stabilization rather than mere binding mechanism via protein half-life.","evidence":"Co-IP, confocal co-localization, VP2 truncation mapping (aa 231–320), cycloheximide chase, and RNAi/inhibitor knockdown with CPV replication assay","pmids":["38384266"],"confidence":"Medium","gaps":["Mechanism of stabilization (folding vs anti-degradation) not distinguished","Role of full chaperonin complex unclear","Single lab"]},{"year":2025,"claim":"Revealed a domain-specific anti-aggregation activity, showing the isolated CCT7 apical domain modulates tau fibril formation independently of holocomplex folding cycles.","evidence":"Kinetic aggregation assays, negative-stain EM, and coarse-grained molecular dynamics simulations comparing CCT7 and CCT3 apical domains","pmids":["40400346"],"confidence":"Medium","gaps":["Activity shown in vitro only, not in cells","Relevance to TRiC holocomplex function unknown","Physiological consequence for tauopathy untested"]},{"year":2025,"claim":"Connected CCT7 to Wnt signaling and stem cell identity by showing it binds and shuttles β-catenin to maintain pluripotency.","evidence":"CCT7 knockout/knockdown in ESCs, Co-IP, nuclear translocation assay, telomere measurement, and RNA-seq/epigenetic profiling","pmids":["41455472"],"confidence":"Medium","gaps":["Whether β-catenin is folded as a chaperone client or carried as a transport partner is unclear","Mechanism linking CCT7 loss to telomere and 2C-state changes not fully resolved","Single lab"]},{"year":2026,"claim":"Identified a non-folding regulatory role in which CCT7 controls autophagy and fibrosis by promoting TRAF6 turnover.","evidence":"Co-IP, ubiquitination assay, siRNA epistasis (TRAF6 KD reversal), autophagy marker quantification, and in vivo knockdown fibrosis model","pmids":["41947340"],"confidence":"Medium","gaps":["How CCT7 promotes TRAF6 ubiquitination (direct E3 recruitment?) is unknown","Whether this is TRiC-dependent is untested","Single disease context"]},{"year":2020,"claim":"Provided a phenotypic link of CCT7 to cancer cell behavior without defining a molecular mechanism.","evidence":"siRNA knockdown with proliferation, apoptosis, and invasion assays in endometrial cancer cell lines","pmids":["32983981"],"confidence":"Low","gaps":["No binding partner or pathway placement identified","Cell-line phenotype only","No in vivo validation"]},{"year":null,"claim":"It remains unresolved which CCT7 activities operate within the intact TRiC/CCT holocomplex versus as autonomous subunit functions, and how its client-folding role mechanistically relates to its TRAF6-directed degradation and β-catenin transport roles.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structural data on CCT7 client complexes","Complex-dependence of non-folding roles unknown","Unifying mechanism across diverse clients not established"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0044183","term_label":"protein folding chaperone","supporting_discovery_ids":[0,2]},{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[5]}],"localization":[{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[0]}],"pathway":[{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[0,2]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[4]},{"term_id":"R-HSA-9612973","term_label":"Autophagy","supporting_discovery_ids":[5]}],"complexes":["TRiC/CCT chaperonin"],"partners":["TBXA2R","ADRB2","CTNNB1","TRAF6"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q99832","full_name":"T-complex protein 1 subunit eta","aliases":["CCT-eta","Chaperonin containing T-complex polypeptide 1 subunit 7","HIV-1 Nef-interacting protein"],"length_aa":543,"mass_kda":59.4,"function":"Component of the chaperonin-containing T-complex (TRiC), a molecular chaperone complex that assists the folding of actin, tubulin and other proteins upon ATP hydrolysis (PubMed:25467444, PubMed:36493755, PubMed:35449234, PubMed:37193829). The TRiC complex mediates the folding of WRAP53/TCAB1, thereby regulating telomere maintenance (PubMed:25467444)","subcellular_location":"Cytoplasm","url":"https://www.uniprot.org/uniprotkb/Q99832/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":true,"resolved_as":"","url":"https://depmap.org/portal/gene/CCT7","classification":"Common Essential","n_dependent_lines":1120,"n_total_lines":1208,"dependency_fraction":0.9271523178807947},"opencell":{"profiled":true,"resolved_as":"","ensg_id":"ENSG00000135624","cell_line_id":"CID000212","localizations":[{"compartment":"cytoplasmic","grade":3},{"compartment":"nucleoplasm","grade":3},{"compartment":"big_aggregates","grade":1}],"interactors":[{"gene":"ACTB","stoichiometry":10.0},{"gene":"CCT2","stoichiometry":10.0},{"gene":"CCT3","stoichiometry":10.0},{"gene":"CCT4","stoichiometry":10.0},{"gene":"CCT5","stoichiometry":10.0},{"gene":"CCT6A","stoichiometry":10.0},{"gene":"TCP1","stoichiometry":10.0},{"gene":"CCT8","stoichiometry":10.0},{"gene":"PDCD5","stoichiometry":10.0},{"gene":"PPP2CA","stoichiometry":10.0}],"url":"https://opencell.sf.czbiohub.org/target/CID000212","total_profiled":1310},"omim":[{"mim_id":"618558","title":"G PROTEIN SIGNALING MODULATOR 3; GPSM3","url":"https://www.omim.org/entry/618558"},{"mim_id":"610150","title":"CHAPERONIN CONTAINING T-COMPLEX POLYPEPTIDE 1, SUBUNIT 5; CCT5","url":"https://www.omim.org/entry/610150"},{"mim_id":"605140","title":"CHAPERONIN CONTAINING T-COMPLEX POLYPEPTIDE 1, SUBUNIT 7; CCT7","url":"https://www.omim.org/entry/605140"},{"mim_id":"605139","title":"CHAPERONIN CONTAINING T-COMPLEX POLYPEPTIDE 1, SUBUNIT 2; CCT2","url":"https://www.omim.org/entry/605139"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Cytosol","reliability":"Approved"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/CCT7"},"hgnc":{"alias_symbol":["Ccth","Nip7-1"],"prev_symbol":[]},"alphafold":{"accession":"Q99832","domains":[{"cath_id":"1.10.560.10","chopping":"13-141_406-520","consensus_level":"medium","plddt":93.3088,"start":13,"end":520},{"cath_id":"3.50.7.10","chopping":"220-366","consensus_level":"high","plddt":89.6211,"start":220,"end":366}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q99832","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q99832-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q99832-F1-predicted_aligned_error_v6.png","plddt_mean":88.88},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=CCT7","jax_strain_url":"https://www.jax.org/strain/search?query=CCT7"},"sequence":{"accession":"Q99832","fasta_url":"https://rest.uniprot.org/uniprotkb/Q99832.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q99832/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q99832"}},"corpus_meta":[{"pmid":"30691230","id":"PMC_30691230","title":"Requirement of Cellular Protein CCT7 for the Replication of Fowl Adenovirus Serotype 4 (FAdV-4) in Leghorn Male Hepatocellular Cells Via Interaction with the Viral Hexon Protein.","date":"2019","source":"Viruses","url":"https://pubmed.ncbi.nlm.nih.gov/30691230","citation_count":25,"is_preprint":false},{"pmid":"18996651","id":"PMC_18996651","title":"Correlating blood immune parameters and a CCT7 genetic variant with the shedding of Salmonella enterica serovar Typhimurium in swine.","date":"2008","source":"Veterinary microbiology","url":"https://pubmed.ncbi.nlm.nih.gov/18996651","citation_count":23,"is_preprint":false},{"pmid":"27708139","id":"PMC_27708139","title":"Regulation of GPCR expression through an interaction with CCT7, a subunit of the CCT/TRiC complex.","date":"2016","source":"Molecular biology of the cell","url":"https://pubmed.ncbi.nlm.nih.gov/27708139","citation_count":20,"is_preprint":false},{"pmid":"32983981","id":"PMC_32983981","title":"Clinical Significance, Cellular Function, and Potential Molecular Pathways of CCT7 in Endometrial Cancer.","date":"2020","source":"Frontiers in oncology","url":"https://pubmed.ncbi.nlm.nih.gov/32983981","citation_count":11,"is_preprint":false},{"pmid":"21937822","id":"PMC_21937822","title":"Intron sequences from the CCT7 gene exhibit diverse evolutionary histories among the four lineages within the Babesia microti-group, a genetically related species complex that includes human pathogens.","date":"2011","source":"Japanese journal of infectious diseases","url":"https://pubmed.ncbi.nlm.nih.gov/21937822","citation_count":10,"is_preprint":false},{"pmid":"8948101","id":"PMC_8948101","title":"Sequencing analysis of a 40.2 kb fragment of yeast chromosome X reveals 19 open reading frames including URA2 (5' end), TRK1, PBS2, SPT10, GCD14, RPE1, PHO86, NCA3, ASF1, CCT7, GZF3, two tRNA genes, three remnant delta elements and a Ty4 transposon.","date":"1996","source":"Yeast (Chichester, England)","url":"https://pubmed.ncbi.nlm.nih.gov/8948101","citation_count":6,"is_preprint":false},{"pmid":"38384266","id":"PMC_38384266","title":"Chaperonin TRiC/CCT subunit CCT7 is involved in the replication of canine parvovirus in F81 cells.","date":"2024","source":"Frontiers in microbiology","url":"https://pubmed.ncbi.nlm.nih.gov/38384266","citation_count":4,"is_preprint":false},{"pmid":"40400346","id":"PMC_40400346","title":"Inhibition of tau aggregation by the CCT3 and CCT7 apical domains.","date":"2025","source":"Protein science : a publication of the Protein Society","url":"https://pubmed.ncbi.nlm.nih.gov/40400346","citation_count":3,"is_preprint":false},{"pmid":"41455472","id":"PMC_41455472","title":"Chaperonin proteins CCT5 and CCT7 epigenetically restrict the transition from pluripotency to totipotency in embryonic stem cells.","date":"2025","source":"Stem cell reports","url":"https://pubmed.ncbi.nlm.nih.gov/41455472","citation_count":1,"is_preprint":false},{"pmid":"41947340","id":"PMC_41947340","title":"CCT7 Regulates TRAF6-Mediated Autophagy to Promote Posttraumatic Joint Contracture.","date":"2026","source":"Journal of cellular and molecular medicine","url":"https://pubmed.ncbi.nlm.nih.gov/41947340","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":6726,"output_tokens":2035,"usd":0.025351,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":9044,"output_tokens":2695,"usd":0.056298,"stage2_stop_reason":"end_turn"},"total_usd":0.081649,"stage1_batch_id":"msgbatch_01ACAxJQabDsht39JXeWG22d","stage2_batch_id":"msgbatch_01QEU22A9U5sbPTgsMzTmvSf","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2016,\n      \"finding\": \"CCT7 (chaperonin containing TCP-1 subunit eta) interacts directly with the thromboxane A2 receptor β-isoform (TPβ) and β2-adrenergic receptor (β2AR) through their third intracellular loops and C-termini, as demonstrated by yeast two-hybrid screening, co-immunoprecipitation, and in vitro pull-down assays. CCT7 depletion by siRNA reduced total and cell-surface expression of both receptors and caused their redistribution to juxtanuclear aggresomes, indicating CCT7/TRiC chaperonin complex is required for proper folding, maturation, and trafficking of nascent GPCRs. Trp334 in the TPβ C-terminus was identified as critical for CCT7 interaction and TPβ maturation.\",\n      \"method\": \"Yeast two-hybrid screening, co-immunoprecipitation, in vitro pull-down assay, siRNA knockdown, site-directed mutagenesis, cell-surface expression assays\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — multiple orthogonal methods (Y2H, Co-IP, in vitro pulldown, mutagenesis, KD phenotype) in single rigorous study\",\n      \"pmids\": [\"27708139\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"CCT7 interacts with the FAdV-4 capsid protein hexon, and is required for viral replication in leghorn male hepatocellular (LMH) cells. Ectopic overexpression of CCT7 enhanced hexon expression, while RNAi-mediated knockdown of CCT7 reduced hexon expression and suppressed FAdV-4 replication.\",\n      \"method\": \"Co-immunoprecipitation (interaction identification), ectopic overexpression, RNAi knockdown with viral replication assay\",\n      \"journal\": \"Viruses\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — Co-IP plus functional KD/OE with clear phenotypic readout, single lab, two complementary methods\",\n      \"pmids\": [\"30691230\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"CCT7 interacts with canine parvovirus capsid protein VP2, with the interaction region mapped to amino acids 231–320 of VP2 by truncation mutant analysis. CCT7 stabilizes VP2 protein (demonstrated by cycloheximide chase), and knockdown of CCT7 by RNAi or HSF1A inhibitor reduced VP2 expression and CPV replication, while CCT7 overexpression increased VP2 levels.\",\n      \"method\": \"Yeast one-to-one assay, co-immunoprecipitation, laser confocal co-localization, VP2 truncation mutant mapping, cycloheximide chase, RNAi knockdown, overexpression\",\n      \"journal\": \"Frontiers in microbiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — multiple orthogonal methods (Co-IP, CHX chase, truncation mapping, KD/OE), single lab\",\n      \"pmids\": [\"38384266\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"The apical domain of CCT7 inhibits tau aggregation in vitro. Kinetic analyses and negative-stain electron microscopy show that aggregation of tau in the presence of the CCT7 apical domain follows a fragmentation model, and coarse-grained molecular dynamics simulations indicate tau interacts with distinct regions of the CCT7 apical domain compared to CCT3, consistent with their different inhibition mechanisms.\",\n      \"method\": \"Kinetic aggregation assays, negative-stain electron microscopy, coarse-grained molecular dynamics simulations\",\n      \"journal\": \"Protein science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — in vitro biochemical assays plus EM and simulation, single lab, multiple orthogonal methods\",\n      \"pmids\": [\"40400346\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"CCT7 directly binds β-catenin and facilitates its nuclear translocation, thereby stabilizing pluripotency through Wnt/β-catenin signaling in embryonic stem cells. CCT7 deficiency disrupts telomere length homeostasis, triggers DNA damage response pathways, induces epigenetic reprogramming, activates repeat elements and 2-cell transcriptional programs, and facilitates transition to a 2-cell-like (totipotent) state.\",\n      \"method\": \"CCT7 knockout/knockdown in ESCs, co-immunoprecipitation (CCT7–β-catenin), nuclear translocation assay, telomere length measurement, RNA-seq/epigenetic assays\",\n      \"journal\": \"Stem cell reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — Co-IP for direct binding, KO functional phenotype with multiple readouts, single lab\",\n      \"pmids\": [\"41455472\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"CCT7 interacts with TRAF6 and facilitates its ubiquitination and degradation, thereby suppressing autophagy (reduced LC3-II, Beclin-1; increased p62) and promoting fibroblast fibrosis. Knockdown of CCT7 in fibroblasts reduced α-SMA and COL-I expression, suppressed fibroblast migration, and enhanced autophagy; these effects were reversed by TRAF6 knockdown, placing CCT7 upstream of TRAF6 in this pathway. In vivo CCT7 knockdown improved joint range of motion and reduced fibrosis.\",\n      \"method\": \"Co-immunoprecipitation (CCT7–TRAF6), ubiquitination assay, siRNA knockdown of CCT7 and TRAF6, autophagy marker quantification, in vivo animal model\",\n      \"journal\": \"Journal of cellular and molecular medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — Co-IP, ubiquitination assay, epistatic rescue (TRAF6 KD reversal), in vivo validation, single lab\",\n      \"pmids\": [\"41947340\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"CCT7 knockdown by siRNA in endometrial cancer cell lines (Ishikawa and RL95-2) suppressed proliferation, promoted apoptosis, and reduced invasion, establishing a functional role for CCT7 in endometrial cancer cell behavior.\",\n      \"method\": \"siRNA knockdown, proliferation assay, apoptosis assay, invasion assay\",\n      \"journal\": \"Frontiers in oncology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — KD with phenotypic readout but no pathway placement or binding partner identification; single lab, single study\",\n      \"pmids\": [\"32983981\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"CCT7 is the eta subunit of the TRiC/CCT chaperonin complex that directly binds and promotes folding/maturation of client proteins including GPCRs (via their intracellular loops and C-termini), viral capsid proteins (hexon, VP2), and β-catenin (facilitating nuclear translocation for Wnt signaling); its apical domain also inhibits tau aggregation through a fragmentation-based mechanism, and it regulates autophagy by binding TRAF6 and promoting its ubiquitination and degradation.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"CCT7 is the eta subunit of the TRiC/CCT chaperonin complex and functions as a chaperone that directly binds nascent or aggregation-prone client proteins to promote their folding, maturation, and trafficking [#0]. It is required for proper folding and cell-surface delivery of G protein-coupled receptors, interacting with the thromboxane A2 receptor β-isoform and the β2-adrenergic receptor through their third intracellular loops and C-termini; loss of CCT7 reduces receptor expression and redirects them to juxtanuclear aggresomes, and Trp334 in the TPβ C-terminus is critical for the interaction [#0]. CCT7 stabilizes viral capsid proteins as folding clients, binding the FAdV-4 hexon and the canine parvovirus VP2 capsid protein to support their accumulation and viral replication [#1, #2]. Through direct binding it also stabilizes and drives nuclear translocation of β-catenin, sustaining Wnt/β-catenin signaling and pluripotency in embryonic stem cells [#4]. Beyond classical chaperone clients, the isolated CCT7 apical domain inhibits tau aggregation in vitro via a fragmentation-based mechanism [#3], and CCT7 suppresses autophagy and promotes fibroblast fibrosis by binding TRAF6 and facilitating its ubiquitination and degradation [#5].\",\n  \"teleology\": [\n    {\n      \"year\": 2016,\n      \"claim\": \"Established CCT7 as a chaperone required for GPCR biogenesis, answering how nascent receptors achieve correct folding and trafficking to the cell surface.\",\n      \"evidence\": \"Yeast two-hybrid, Co-IP, in vitro pull-down, site-directed mutagenesis, and siRNA knockdown with cell-surface expression assays for TPβ and β2AR\",\n      \"pmids\": [\"27708139\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Whether folding requires the full TRiC/CCT complex or CCT7 alone is not resolved\",\n        \"No structural model of the CCT7–receptor interface\",\n        \"Generality across other GPCR families not tested\"\n      ]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Extended CCT7 client repertoire to viral structural proteins, showing it supports adenoviral capsid protein expression and replication.\",\n      \"evidence\": \"Co-IP plus ectopic overexpression and RNAi knockdown with FAdV-4 replication readout in LMH cells\",\n      \"pmids\": [\"30691230\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Direct folding/chaperone activity on hexon not demonstrated biochemically\",\n        \"Interaction interface on hexon not mapped\",\n        \"Single cell system\"\n      ]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Demonstrated CCT7 stabilizes a second viral capsid protein, defining a stabilization rather than mere binding mechanism via protein half-life.\",\n      \"evidence\": \"Co-IP, confocal co-localization, VP2 truncation mapping (aa 231–320), cycloheximide chase, and RNAi/inhibitor knockdown with CPV replication assay\",\n      \"pmids\": [\"38384266\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Mechanism of stabilization (folding vs anti-degradation) not distinguished\",\n        \"Role of full chaperonin complex unclear\",\n        \"Single lab\"\n      ]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Revealed a domain-specific anti-aggregation activity, showing the isolated CCT7 apical domain modulates tau fibril formation independently of holocomplex folding cycles.\",\n      \"evidence\": \"Kinetic aggregation assays, negative-stain EM, and coarse-grained molecular dynamics simulations comparing CCT7 and CCT3 apical domains\",\n      \"pmids\": [\"40400346\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Activity shown in vitro only, not in cells\",\n        \"Relevance to TRiC holocomplex function unknown\",\n        \"Physiological consequence for tauopathy untested\"\n      ]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Connected CCT7 to Wnt signaling and stem cell identity by showing it binds and shuttles β-catenin to maintain pluripotency.\",\n      \"evidence\": \"CCT7 knockout/knockdown in ESCs, Co-IP, nuclear translocation assay, telomere measurement, and RNA-seq/epigenetic profiling\",\n      \"pmids\": [\"41455472\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Whether β-catenin is folded as a chaperone client or carried as a transport partner is unclear\",\n        \"Mechanism linking CCT7 loss to telomere and 2C-state changes not fully resolved\",\n        \"Single lab\"\n      ]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Identified a non-folding regulatory role in which CCT7 controls autophagy and fibrosis by promoting TRAF6 turnover.\",\n      \"evidence\": \"Co-IP, ubiquitination assay, siRNA epistasis (TRAF6 KD reversal), autophagy marker quantification, and in vivo knockdown fibrosis model\",\n      \"pmids\": [\"41947340\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"How CCT7 promotes TRAF6 ubiquitination (direct E3 recruitment?) is unknown\",\n        \"Whether this is TRiC-dependent is untested\",\n        \"Single disease context\"\n      ]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Provided a phenotypic link of CCT7 to cancer cell behavior without defining a molecular mechanism.\",\n      \"evidence\": \"siRNA knockdown with proliferation, apoptosis, and invasion assays in endometrial cancer cell lines\",\n      \"pmids\": [\"32983981\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"No binding partner or pathway placement identified\",\n        \"Cell-line phenotype only\",\n        \"No in vivo validation\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"It remains unresolved which CCT7 activities operate within the intact TRiC/CCT holocomplex versus as autonomous subunit functions, and how its client-folding role mechanistically relates to its TRAF6-directed degradation and β-catenin transport roles.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"No structural data on CCT7 client complexes\",\n        \"Complex-dependence of non-folding roles unknown\",\n        \"Unifying mechanism across diverse clients not established\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0044183\", \"supporting_discovery_ids\": [0, 2]},\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [5]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [0, 2]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [4]},\n      {\"term_id\": \"R-HSA-9612973\", \"supporting_discovery_ids\": [5]}\n    ],\n    \"complexes\": [\"TRiC/CCT chaperonin\"],\n    \"partners\": [\"TBXA2R\", \"ADRB2\", \"CTNNB1\", \"TRAF6\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":5,"faith_total":5,"faith_pct":100.0}}