{"gene":"CCT8","run_date":"2026-06-09T22:57:17","timeline":{"discoveries":[{"year":1995,"finding":"CCT8 (Cctq) encodes the theta subunit of the cytosolic chaperonin CCT/TRiC complex; the protein contains motifs common to all CCT subunits postulated to be involved in ATPase activity, and assembles into the heterooligomeric CCT complex as confirmed by 2D gel analysis of the native complex.","method":"cDNA cloning, antibody-based 2D gel analysis of native CCT complex, sequence motif analysis","journal":"Gene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — identification of subunit membership by native complex co-fractionation and 2D gel, single lab, multiple methods","pmids":["7890169"],"is_preprint":false},{"year":2003,"finding":"Transcription of the CCT8 (Cctq) gene is regulated by ternary complex factors (TCFs) Elk-1, Sap-1a, and Net binding to a cis-element (CQE1 at -36 bp) in the promoter, under control of the Ras/MAPK pathway and independently of serum response factor.","method":"Reporter gene assay, EMSA with anti-Elk-1/Sap-1a antibodies, recombinant TCF binding, MAPK inhibitor (PD98059) treatment, overexpression of dominant-negative TCF DNA-binding domains","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — multiple orthogonal methods (reporter assay, EMSA, inhibitor, dominant-negative) in one study establishing transcriptional mechanism","pmids":["12788937"],"is_preprint":false},{"year":2016,"finding":"Ectopic expression of CCT8 alone is sufficient to increase assembly of the TRiC/CCT complex; elevated TRiC/CCT is required to prevent aggregation of mutant Huntingtin protein in human pluripotent stem cells and somatic cells.","method":"Ectopic CCT8 overexpression in human cells, native complex assembly assays, mutant Huntingtin aggregation assay, C. elegans lifespan extension with CCT-dependent genetic validation","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods across mammalian and C. elegans systems, epistasis (TRiC-dependent rescue), replicated mechanistic outcome","pmids":["27892468"],"is_preprint":false},{"year":2014,"finding":"CCT8 depletion by siRNA inhibits cell proliferation and blocks S-phase entry in HuH7 hepatocellular carcinoma cells, establishing a role for CCT8 in cell cycle progression.","method":"siRNA knockdown, cell proliferation assay, flow cytometry cell cycle analysis","journal":"APMIS","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — clean KD with defined cell-cycle phenotype, single lab, two methods","pmids":["24862099"],"is_preprint":false},{"year":2015,"finding":"CCT8 silencing in U87 and U251MG glioblastoma cells decreases proliferation, invasion capacity, and causes dysregulation of the cell cytoskeleton, placing CCT8 upstream of cytoskeletal organization and invasive behavior.","method":"siRNA knockdown, CCK8 assay, flow cytometry, scratch assay, transwell invasion assay, fluorescence cytoskeleton imaging","journal":"Pathology, research and practice","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — KD with multiple phenotypic readouts including cytoskeleton, single lab","pmids":["26304164"],"is_preprint":false},{"year":2015,"finding":"GRP94 knockdown attenuates HCC cell migration and invasion by downregulating CCT8/c-Jun/EMT signaling, placing CCT8 downstream of GRP94 in a metastatic signaling cascade.","method":"shRNA knockdown of GRP94, wound-healing assay, transwell migration/invasion assay, western blot for CCT8 and c-Jun","journal":"Tumour biology","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — epistasis by KD showing GRP94→CCT8→c-Jun pathway, single lab, multiple functional assays","pmids":["26718209"],"is_preprint":false},{"year":2021,"finding":"CCT8 interacts with LASP1 in colorectal cancer cells and inhibits nuclear entry of wild-type p53 (WTp53), thereby promoting cell cycle progression and EMT; negative correlation between CCT8 expression and nuclear WTp53 was confirmed in clinical tissue.","method":"Co-immunoprecipitation (CCT8–LASP1 interaction), in vitro and in vivo invasion/proliferation assays, nuclear fractionation/immunofluorescence for WTp53 localization, clinical tissue correlation","journal":"Oncogenesis","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — Co-IP for interaction, fractionation for p53 nuclear exclusion, functional assays, single lab","pmids":["34862361"],"is_preprint":false},{"year":2021,"finding":"In T cells, absence of the CCT complex (conditional CCT8 deletion) impairs formation of nuclear actin filaments and a normal stress response, blocks thymocyte maturation and selection, impairs homeostatic maintenance and TCR-mediated activation, and causes aberrant Th2 polarization with continued IFN-γ expression, resulting in failure to protect against helminths.","method":"Conditional knockout in mice, proteomics of CCT-deficient T cells, nuclear actin filament imaging, T cell activation assays, in vivo helminth infection model","journal":"Communications biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — conditional KO with multiple orthogonal phenotypic readouts (proteomics, imaging, activation, in vivo immunity), single study but comprehensive","pmids":["34083746"],"is_preprint":false},{"year":2023,"finding":"CCT8 interacts with and activates AKT; inhibition of AKT suppresses CCT8-induced cell migration and tumor metastasis in lung adenocarcinoma cells, placing CCT8 upstream of AKT in a pro-metastatic pathway.","method":"Co-immunoprecipitation, ectopic CCT8 overexpression and knockdown, migration assays, AKT inhibitor rescue experiment, in vivo metastasis model","journal":"Journal of Cancer","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — Co-IP for CCT8-AKT interaction, AKT inhibitor epistasis, functional assays, single lab","pmids":["37928427"],"is_preprint":false},{"year":2025,"finding":"CCT8 interacts with TULP2 via its apical domain; CCT8 knockdown causes TULP2 aggregation in the cytoplasm, impairing TULP2 function in ciliogenesis, identifying TULP2 as a CCT8 substrate required for intraflagellar transport during spermiogenesis.","method":"Co-immunoprecipitation (CCT8 apical domain–TULP2), CCT8 knockdown with TULP2 aggregation readout, localization analysis of IFT components in KO mice, identification of human TULP2 variant in infertility patient","journal":"Biology of reproduction","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP mapping of interaction domain, KD showing substrate aggregation, in vivo KO phenotype, single lab","pmids":["40613306"],"is_preprint":false},{"year":2025,"finding":"CCT8 is a client of the FKBP4-Hsp90 co-chaperone complex; knockdown of FKBP4 leads to CCT8 aggregation and compromises stability of CCT8 clients CDK2 and α-tubulin, revealing functional crosstalk between the Hsp90 and CCT/chaperonin folding systems.","method":"BioID proximity-labeling mass spectrometry, FKBP4 knockdown, CCT8 aggregation assay, client stability western blot (CDK2, α-tubulin)","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — BioID proteomics plus KD with aggregation and client stability readouts, single lab, two orthogonal methods","pmids":["41203126"],"is_preprint":false},{"year":2025,"finding":"CCT8 interacts with the influenza A H9N2 PB2 protein; CCT8 knockdown inhibits viral proliferation, and elevated CCT8 expression facilitates viral proliferation, establishing CCT8 as a host factor required for influenza virus replication.","method":"Co-immunoprecipitation (CCT8–PB2), CCT8 knockdown and overexpression with viral titer readout","journal":"Avian pathology","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — Co-IP plus KD/OE with viral replication phenotype, single lab","pmids":["40135264"],"is_preprint":false},{"year":2025,"finding":"CCT8 interacts with RPL4 in colorectal cancer cells; co-immunoprecipitation confirmed this interaction, and the CCT8/RPL4 axis influences the MDM2-p53 pathway contributing to p53 ubiquitination and degradation.","method":"Co-immunoprecipitation (CCT8–RPL4), functional assays (CCK-8, transwell, wound-healing, flow cytometry), gene set enrichment analysis, protein-protein interaction network analysis","journal":"BMC medical genomics","confidence":"Low","confidence_rationale":"Tier 3 / Weak — Co-IP in single study, p53 ubiquitination and degradation mechanism inferred from correlation/bioinformatics rather than direct biochemical demonstration","pmids":["40251552"],"is_preprint":false}],"current_model":"CCT8 is the theta subunit of the hetero-oligomeric cytosolic chaperonin TRiC/CCT complex; its expression is transcriptionally driven by Elk-1/Sap-1a/Net TCFs via the Ras/MAPK pathway, and its ectopic overexpression is sufficient to boost TRiC/CCT assembly, preventing mutant Huntingtin aggregation and extending lifespan in a TRiC-dependent manner; in somatic cells CCT8 folds clients including TULP2, CDK2, and α-tubulin (itself requiring the FKBP4-Hsp90 system for proper folding), promotes cell cycle progression and cytoskeletal organization, interacts with LASP1 to sequester p53 from the nucleus and drive EMT, activates AKT to promote cell migration and metastasis, is required for T cell development and activation through proteostasis control, and facilitates influenza virus replication by interacting with the viral PB2 protein."},"narrative":{"mechanistic_narrative":"CCT8 is the theta subunit of the hetero-oligomeric cytosolic chaperonin CCT/TRiC complex, contributing ATPase-associated motifs shared across CCT subunits and assembling into the native heterooligomeric complex [PMID:7890169]. Its expression is transcriptionally controlled by the ternary complex factors Elk-1, Sap-1a, and Net binding a promoter cis-element under Ras/MAPK control [PMID:12788937]. Strikingly, ectopic CCT8 alone is sufficient to drive assembly of the full TRiC/CCT complex, and the resulting elevated chaperonin activity prevents aggregation of mutant Huntingtin and confers TRiC-dependent proteostatic protection [PMID:27892468]. As a folding machine CCT8 chaperones specific clients, including TULP2 — which it engages through its apical domain and whose loss causes cytoplasmic aggregation and defective ciliogenesis [PMID:40613306] — while CCT8 itself depends on the FKBP4-Hsp90 co-chaperone system, linking the Hsp90 and chaperonin folding pathways and stabilizing downstream clients CDK2 and α-tubulin [PMID:41203126]. Through this proteostatic role CCT8 supports cell cycle progression and cytoskeletal organization [PMID:24862099, PMID:26304164] and is required for thymocyte maturation, T cell activation, and protective immunity [PMID:34083746]. In cancer, CCT8 acts in pro-tumorigenic signaling: it binds LASP1 to exclude wild-type p53 from the nucleus and promote EMT [PMID:34862361], interacts with and activates AKT to drive migration and metastasis [PMID:37928427], and functions downstream of GRP94 in a c-Jun/EMT cascade [PMID:26718209]. CCT8 also serves as a host factor for influenza A replication via interaction with the viral PB2 protein [PMID:40135264].","teleology":[{"year":1995,"claim":"Established CCT8 as a bona fide subunit of the cytosolic chaperonin rather than a free-standing protein, defining its molecular identity.","evidence":"cDNA cloning, sequence motif analysis, and 2D gel analysis of the native CCT complex","pmids":["7890169"],"confidence":"Medium","gaps":["ATPase activity inferred from motifs, not directly measured","subunit stoichiometry and arrangement within the complex not resolved"]},{"year":2003,"claim":"Answered how CCT8 expression is controlled, linking chaperonin subunit levels to mitogenic Ras/MAPK signaling through specific TCF transcription factors.","evidence":"Reporter assays, EMSA, MAPK inhibitor, and dominant-negative TCF constructs on the promoter","pmids":["12788937"],"confidence":"High","gaps":["downstream physiological consequences of TCF-driven CCT8 induction not tested","whether other CCT subunits are co-regulated unknown"]},{"year":2016,"claim":"Demonstrated that CCT8 is rate-limiting for TRiC/CCT assembly and that boosting it has functional proteostatic consequences, reframing a single subunit as a lever on whole-complex activity.","evidence":"Ectopic CCT8 overexpression, native assembly assays, mutant Huntingtin aggregation readout, and TRiC-dependent C. elegans lifespan extension","pmids":["27892468"],"confidence":"High","gaps":["structural basis for how excess CCT8 nucleates assembly not defined","client spectrum protected by elevated TRiC not enumerated"]},{"year":2014,"claim":"Connected CCT8 loss to a defined cell-cycle phenotype, implicating chaperonin function in S-phase entry.","evidence":"siRNA knockdown with proliferation assays and flow cytometry in hepatocellular carcinoma cells","pmids":["24862099"],"confidence":"Medium","gaps":["client(s) responsible for S-phase block not identified at this stage","single cell line"]},{"year":2015,"claim":"Extended CCT8's cellular role to cytoskeletal organization and invasion, and positioned it within a GRP94-driven metastatic cascade.","evidence":"siRNA/shRNA knockdown, invasion and migration assays, cytoskeleton imaging, and western blot for c-Jun/EMT markers in glioblastoma and HCC cells","pmids":["26304164","26718209"],"confidence":"Medium","gaps":["direct biochemical link between CCT8 and GRP94 not shown","molecular mechanism connecting CCT8 to c-Jun unresolved"]},{"year":2021,"claim":"Identified specific physical partners (LASP1) and a signaling output, showing CCT8 controls p53 subcellular localization to drive EMT.","evidence":"Co-immunoprecipitation, nuclear fractionation/immunofluorescence for p53, functional assays, and clinical tissue correlation","pmids":["34862361"],"confidence":"Medium","gaps":["mechanism by which the CCT8-LASP1 interaction excludes p53 not defined","whether p53 is a folding client unknown"]},{"year":2021,"claim":"Established the physiological requirement for CCT chaperonin in adaptive immunity, linking proteostasis to T cell development, activation, and protective responses.","evidence":"Conditional CCT8 knockout in mice, proteomics, nuclear actin imaging, activation assays, and in vivo helminth infection","pmids":["34083746"],"confidence":"High","gaps":["which T-cell client proteins are misfolded upon CCT loss not fully mapped","mechanism of aberrant Th2 polarization not resolved"]},{"year":2023,"claim":"Placed CCT8 upstream of AKT in a pro-metastatic signaling axis, expanding its tumorigenic function beyond folding.","evidence":"Co-immunoprecipitation, overexpression/knockdown, AKT inhibitor rescue, and in vivo metastasis model in lung adenocarcinoma","pmids":["37928427"],"confidence":"Medium","gaps":["whether AKT activation is direct or chaperone-mediated unclear","structural detail of CCT8-AKT interaction absent"]},{"year":2025,"claim":"Defined a specific folding client (TULP2) engaged through the CCT8 apical domain, linking CCT8 to ciliogenesis and male fertility.","evidence":"Co-IP domain mapping, knockdown aggregation assay, IFT localization in KO mice, and a human TULP2 infertility variant","pmids":["40613306"],"confidence":"Medium","gaps":["ATP-dependence of TULP2 folding cycle not shown","whole-complex vs CCT8-specific contribution to TULP2 folding unresolved"]},{"year":2025,"claim":"Revealed crosstalk between Hsp90 and chaperonin systems by showing CCT8 itself is an FKBP4-Hsp90 client whose stability gates downstream clients.","evidence":"BioID proximity labeling, FKBP4 knockdown, CCT8 aggregation assay, and client stability blots (CDK2, α-tubulin)","pmids":["41203126"],"confidence":"Medium","gaps":["whether FKBP4-Hsp90 acts on free CCT8 or assembled complex unknown","generality across CCT subunits untested"]},{"year":2025,"claim":"Identified CCT8 as a host dependency factor for influenza A through interaction with viral PB2.","evidence":"Co-immunoprecipitation and knockdown/overexpression with viral titer readouts","pmids":["40135264"],"confidence":"Medium","gaps":["whether PB2 is folded by CCT8 or merely bound unclear","single viral subtype tested"]},{"year":2025,"claim":"Proposed a CCT8-RPL4 interaction feeding into MDM2-p53 control of p53 degradation in colorectal cancer.","evidence":"Co-immunoprecipitation plus functional assays and bioinformatic network analysis","pmids":["40251552"],"confidence":"Low","gaps":["p53 ubiquitination/degradation mechanism inferred from correlation, not directly demonstrated","RPL4 interaction not reciprocally validated"]},{"year":null,"claim":"How CCT8-specific client selection and apical-domain recognition relate to whole-complex TRiC folding cycles, and how its many signaling outputs (AKT, p53, EMT) emerge mechanistically from chaperonin function, remain unresolved.","evidence":"","pmids":[],"confidence":"Low","gaps":["no structural model of CCT8 client engagement within the assembled complex","distinction between folding-dependent and folding-independent signaling roles not drawn","comprehensive client repertoire undefined"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0044183","term_label":"protein folding chaperone","supporting_discovery_ids":[0,2,9,10]},{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[9,10]}],"localization":[{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[0,9]}],"pathway":[{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[2,9,10]},{"term_id":"R-HSA-1640170","term_label":"Cell Cycle","supporting_discovery_ids":[3,6]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[7]}],"complexes":["TRiC/CCT chaperonin complex"],"partners":["LASP1","AKT","TULP2","FKBP4","RPL4","PB2 (INFLUENZA A)"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"P50990","full_name":"T-complex protein 1 subunit theta","aliases":["CCT-theta","Chaperonin containing T-complex polypeptide 1 subunit 8","Renal carcinoma antigen NY-REN-15"],"length_aa":548,"mass_kda":59.6,"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). As part of the TRiC complex may play a role in the assembly of BBSome, a complex involved in ciliogenesis regulating transports vesicles to the cilia (PubMed:20080638)","subcellular_location":"Cytoplasm; Cytoplasm, cytoskeleton, microtubule organizing center, centrosome; Cytoplasm, cytoskeleton, cilium basal body","url":"https://www.uniprot.org/uniprotkb/P50990/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":true,"resolved_as":"","url":"https://depmap.org/portal/gene/CCT8","classification":"Common Essential","n_dependent_lines":1195,"n_total_lines":1208,"dependency_fraction":0.9892384105960265},"opencell":{"profiled":true,"resolved_as":"","ensg_id":"ENSG00000156261","cell_line_id":"CID000213","localizations":[{"compartment":"cytoplasmic","grade":3},{"compartment":"nucleoplasm","grade":3}],"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":"CCT7","stoichiometry":10.0},{"gene":"PDCD5","stoichiometry":10.0},{"gene":"TCP1","stoichiometry":10.0},{"gene":"PPP2CA","stoichiometry":10.0}],"url":"https://opencell.sf.czbiohub.org/target/CID000213","total_profiled":1310},"omim":[{"mim_id":"617786","title":"CHAPERONIN CONTAINING T-COMPLEX POLYPEPTIDE 1, SUBUNIT 8; CCT8","url":"https://www.omim.org/entry/617786"},{"mim_id":"603331","title":"DYNEIN, CYTOPLASMIC 1, INTERMEDIATE CHAIN 2; DYNC1I2","url":"https://www.omim.org/entry/603331"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Uncertain","locations":[{"location":"Nucleoplasm","reliability":"Uncertain"},{"location":"Connecting piece","reliability":"Uncertain"},{"location":"End piece","reliability":"Uncertain"},{"location":"Cytosol","reliability":"Additional"},{"location":"Mid piece","reliability":"Additional"},{"location":"Principal piece","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/CCT8"},"hgnc":{"alias_symbol":["Cctq","PRED71"],"prev_symbol":["C21orf112"]},"alphafold":{"accession":"P50990","domains":[{"cath_id":"1.10.560.10","chopping":"10-147_409-525","consensus_level":"high","plddt":90.0364,"start":10,"end":525},{"cath_id":"-","chopping":"152-196_384-405","consensus_level":"medium","plddt":87.5199,"start":152,"end":405},{"cath_id":"3.50.7.10","chopping":"215-379","consensus_level":"high","plddt":90.0445,"start":215,"end":379}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P50990","model_url":"https://alphafold.ebi.ac.uk/files/AF-P50990-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P50990-F1-predicted_aligned_error_v6.png","plddt_mean":87.69},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=CCT8","jax_strain_url":"https://www.jax.org/strain/search?query=CCT8"},"sequence":{"accession":"P50990","fasta_url":"https://rest.uniprot.org/uniprotkb/P50990.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P50990/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P50990"}},"corpus_meta":[{"pmid":"27892468","id":"PMC_27892468","title":"Somatic increase of CCT8 mimics proteostasis of human pluripotent stem cells and extends C. elegans lifespan.","date":"2016","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/27892468","citation_count":77,"is_preprint":false},{"pmid":"7890169","id":"PMC_7890169","title":"The eighth Cct gene, Cctq, encoding the theta subunit of the cytosolic chaperonin containing TCP-1.","date":"1995","source":"Gene","url":"https://pubmed.ncbi.nlm.nih.gov/7890169","citation_count":74,"is_preprint":false},{"pmid":"24862099","id":"PMC_24862099","title":"Chaperonin containing TCP1, subunit 8 (CCT8) is upregulated in hepatocellular carcinoma and promotes HCC proliferation.","date":"2014","source":"APMIS : acta pathologica, microbiologica, et immunologica Scandinavica","url":"https://pubmed.ncbi.nlm.nih.gov/24862099","citation_count":61,"is_preprint":false},{"pmid":"21529916","id":"PMC_21529916","title":"Association of CRISP2, CCT8, PEBP1 mRNA abundance in sperm and sire conception rate in Holstein bulls.","date":"2011","source":"Theriogenology","url":"https://pubmed.ncbi.nlm.nih.gov/21529916","citation_count":48,"is_preprint":false},{"pmid":"26304164","id":"PMC_26304164","title":"Overexpression of CCT8 and its significance for tumor cell proliferation, migration and invasion in glioma.","date":"2015","source":"Pathology, research and practice","url":"https://pubmed.ncbi.nlm.nih.gov/26304164","citation_count":42,"is_preprint":false},{"pmid":"34862361","id":"PMC_34862361","title":"CCT8 recovers WTp53-suppressed cell cycle evolution and EMT to promote colorectal cancer progression.","date":"2021","source":"Oncogenesis","url":"https://pubmed.ncbi.nlm.nih.gov/34862361","citation_count":29,"is_preprint":false},{"pmid":"26718209","id":"PMC_26718209","title":"Glucose-regulated protein 94 mediates metastasis by CCT8 and the JNK pathway in hepatocellular carcinoma.","date":"2015","source":"Tumour biology : the journal of the International Society for Oncodevelopmental Biology and 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pathology : journal of the W.V.P.A","url":"https://pubmed.ncbi.nlm.nih.gov/40135264","citation_count":1,"is_preprint":false},{"pmid":"40613306","id":"PMC_40613306","title":"TUB-like protein 2, a substrate of CCT8, is essential for the intraflagellar transport during spermiogenesis in mice†.","date":"2025","source":"Biology of reproduction","url":"https://pubmed.ncbi.nlm.nih.gov/40613306","citation_count":1,"is_preprint":false},{"pmid":"41203126","id":"PMC_41203126","title":"Hsp90 co-chaperone FKBP4 facilitates CCT8 folding and connects Hsp90 to chaperonin-dependent proteostasis.","date":"2025","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/41203126","citation_count":0,"is_preprint":false},{"pmid":"40302815","id":"PMC_40302815","title":"Erratum: CCT8 promotes cell migration and tumor metastasis in lung adenocarcinomas: Erratum.","date":"2025","source":"Journal of Cancer","url":"https://pubmed.ncbi.nlm.nih.gov/40302815","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":12117,"output_tokens":3163,"usd":0.041898,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":10637,"output_tokens":3740,"usd":0.073343,"stage2_stop_reason":"end_turn"},"total_usd":0.115241,"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\": 1995,\n      \"finding\": \"CCT8 (Cctq) encodes the theta subunit of the cytosolic chaperonin CCT/TRiC complex; the protein contains motifs common to all CCT subunits postulated to be involved in ATPase activity, and assembles into the heterooligomeric CCT complex as confirmed by 2D gel analysis of the native complex.\",\n      \"method\": \"cDNA cloning, antibody-based 2D gel analysis of native CCT complex, sequence motif analysis\",\n      \"journal\": \"Gene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — identification of subunit membership by native complex co-fractionation and 2D gel, single lab, multiple methods\",\n      \"pmids\": [\"7890169\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"Transcription of the CCT8 (Cctq) gene is regulated by ternary complex factors (TCFs) Elk-1, Sap-1a, and Net binding to a cis-element (CQE1 at -36 bp) in the promoter, under control of the Ras/MAPK pathway and independently of serum response factor.\",\n      \"method\": \"Reporter gene assay, EMSA with anti-Elk-1/Sap-1a antibodies, recombinant TCF binding, MAPK inhibitor (PD98059) treatment, overexpression of dominant-negative TCF DNA-binding domains\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — multiple orthogonal methods (reporter assay, EMSA, inhibitor, dominant-negative) in one study establishing transcriptional mechanism\",\n      \"pmids\": [\"12788937\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Ectopic expression of CCT8 alone is sufficient to increase assembly of the TRiC/CCT complex; elevated TRiC/CCT is required to prevent aggregation of mutant Huntingtin protein in human pluripotent stem cells and somatic cells.\",\n      \"method\": \"Ectopic CCT8 overexpression in human cells, native complex assembly assays, mutant Huntingtin aggregation assay, C. elegans lifespan extension with CCT-dependent genetic validation\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods across mammalian and C. elegans systems, epistasis (TRiC-dependent rescue), replicated mechanistic outcome\",\n      \"pmids\": [\"27892468\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"CCT8 depletion by siRNA inhibits cell proliferation and blocks S-phase entry in HuH7 hepatocellular carcinoma cells, establishing a role for CCT8 in cell cycle progression.\",\n      \"method\": \"siRNA knockdown, cell proliferation assay, flow cytometry cell cycle analysis\",\n      \"journal\": \"APMIS\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — clean KD with defined cell-cycle phenotype, single lab, two methods\",\n      \"pmids\": [\"24862099\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"CCT8 silencing in U87 and U251MG glioblastoma cells decreases proliferation, invasion capacity, and causes dysregulation of the cell cytoskeleton, placing CCT8 upstream of cytoskeletal organization and invasive behavior.\",\n      \"method\": \"siRNA knockdown, CCK8 assay, flow cytometry, scratch assay, transwell invasion assay, fluorescence cytoskeleton imaging\",\n      \"journal\": \"Pathology, research and practice\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — KD with multiple phenotypic readouts including cytoskeleton, single lab\",\n      \"pmids\": [\"26304164\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"GRP94 knockdown attenuates HCC cell migration and invasion by downregulating CCT8/c-Jun/EMT signaling, placing CCT8 downstream of GRP94 in a metastatic signaling cascade.\",\n      \"method\": \"shRNA knockdown of GRP94, wound-healing assay, transwell migration/invasion assay, western blot for CCT8 and c-Jun\",\n      \"journal\": \"Tumour biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — epistasis by KD showing GRP94→CCT8→c-Jun pathway, single lab, multiple functional assays\",\n      \"pmids\": [\"26718209\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"CCT8 interacts with LASP1 in colorectal cancer cells and inhibits nuclear entry of wild-type p53 (WTp53), thereby promoting cell cycle progression and EMT; negative correlation between CCT8 expression and nuclear WTp53 was confirmed in clinical tissue.\",\n      \"method\": \"Co-immunoprecipitation (CCT8–LASP1 interaction), in vitro and in vivo invasion/proliferation assays, nuclear fractionation/immunofluorescence for WTp53 localization, clinical tissue correlation\",\n      \"journal\": \"Oncogenesis\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — Co-IP for interaction, fractionation for p53 nuclear exclusion, functional assays, single lab\",\n      \"pmids\": [\"34862361\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"In T cells, absence of the CCT complex (conditional CCT8 deletion) impairs formation of nuclear actin filaments and a normal stress response, blocks thymocyte maturation and selection, impairs homeostatic maintenance and TCR-mediated activation, and causes aberrant Th2 polarization with continued IFN-γ expression, resulting in failure to protect against helminths.\",\n      \"method\": \"Conditional knockout in mice, proteomics of CCT-deficient T cells, nuclear actin filament imaging, T cell activation assays, in vivo helminth infection model\",\n      \"journal\": \"Communications biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — conditional KO with multiple orthogonal phenotypic readouts (proteomics, imaging, activation, in vivo immunity), single study but comprehensive\",\n      \"pmids\": [\"34083746\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"CCT8 interacts with and activates AKT; inhibition of AKT suppresses CCT8-induced cell migration and tumor metastasis in lung adenocarcinoma cells, placing CCT8 upstream of AKT in a pro-metastatic pathway.\",\n      \"method\": \"Co-immunoprecipitation, ectopic CCT8 overexpression and knockdown, migration assays, AKT inhibitor rescue experiment, in vivo metastasis model\",\n      \"journal\": \"Journal of Cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — Co-IP for CCT8-AKT interaction, AKT inhibitor epistasis, functional assays, single lab\",\n      \"pmids\": [\"37928427\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"CCT8 interacts with TULP2 via its apical domain; CCT8 knockdown causes TULP2 aggregation in the cytoplasm, impairing TULP2 function in ciliogenesis, identifying TULP2 as a CCT8 substrate required for intraflagellar transport during spermiogenesis.\",\n      \"method\": \"Co-immunoprecipitation (CCT8 apical domain–TULP2), CCT8 knockdown with TULP2 aggregation readout, localization analysis of IFT components in KO mice, identification of human TULP2 variant in infertility patient\",\n      \"journal\": \"Biology of reproduction\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP mapping of interaction domain, KD showing substrate aggregation, in vivo KO phenotype, single lab\",\n      \"pmids\": [\"40613306\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"CCT8 is a client of the FKBP4-Hsp90 co-chaperone complex; knockdown of FKBP4 leads to CCT8 aggregation and compromises stability of CCT8 clients CDK2 and α-tubulin, revealing functional crosstalk between the Hsp90 and CCT/chaperonin folding systems.\",\n      \"method\": \"BioID proximity-labeling mass spectrometry, FKBP4 knockdown, CCT8 aggregation assay, client stability western blot (CDK2, α-tubulin)\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — BioID proteomics plus KD with aggregation and client stability readouts, single lab, two orthogonal methods\",\n      \"pmids\": [\"41203126\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"CCT8 interacts with the influenza A H9N2 PB2 protein; CCT8 knockdown inhibits viral proliferation, and elevated CCT8 expression facilitates viral proliferation, establishing CCT8 as a host factor required for influenza virus replication.\",\n      \"method\": \"Co-immunoprecipitation (CCT8–PB2), CCT8 knockdown and overexpression with viral titer readout\",\n      \"journal\": \"Avian pathology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — Co-IP plus KD/OE with viral replication phenotype, single lab\",\n      \"pmids\": [\"40135264\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"CCT8 interacts with RPL4 in colorectal cancer cells; co-immunoprecipitation confirmed this interaction, and the CCT8/RPL4 axis influences the MDM2-p53 pathway contributing to p53 ubiquitination and degradation.\",\n      \"method\": \"Co-immunoprecipitation (CCT8–RPL4), functional assays (CCK-8, transwell, wound-healing, flow cytometry), gene set enrichment analysis, protein-protein interaction network analysis\",\n      \"journal\": \"BMC medical genomics\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — Co-IP in single study, p53 ubiquitination and degradation mechanism inferred from correlation/bioinformatics rather than direct biochemical demonstration\",\n      \"pmids\": [\"40251552\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"CCT8 is the theta subunit of the hetero-oligomeric cytosolic chaperonin TRiC/CCT complex; its expression is transcriptionally driven by Elk-1/Sap-1a/Net TCFs via the Ras/MAPK pathway, and its ectopic overexpression is sufficient to boost TRiC/CCT assembly, preventing mutant Huntingtin aggregation and extending lifespan in a TRiC-dependent manner; in somatic cells CCT8 folds clients including TULP2, CDK2, and α-tubulin (itself requiring the FKBP4-Hsp90 system for proper folding), promotes cell cycle progression and cytoskeletal organization, interacts with LASP1 to sequester p53 from the nucleus and drive EMT, activates AKT to promote cell migration and metastasis, is required for T cell development and activation through proteostasis control, and facilitates influenza virus replication by interacting with the viral PB2 protein.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"CCT8 is the theta subunit of the hetero-oligomeric cytosolic chaperonin CCT/TRiC complex, contributing ATPase-associated motifs shared across CCT subunits and assembling into the native heterooligomeric complex [#0]. Its expression is transcriptionally controlled by the ternary complex factors Elk-1, Sap-1a, and Net binding a promoter cis-element under Ras/MAPK control [#1]. Strikingly, ectopic CCT8 alone is sufficient to drive assembly of the full TRiC/CCT complex, and the resulting elevated chaperonin activity prevents aggregation of mutant Huntingtin and confers TRiC-dependent proteostatic protection [#2]. As a folding machine CCT8 chaperones specific clients, including TULP2 — which it engages through its apical domain and whose loss causes cytoplasmic aggregation and defective ciliogenesis [#9] — while CCT8 itself depends on the FKBP4-Hsp90 co-chaperone system, linking the Hsp90 and chaperonin folding pathways and stabilizing downstream clients CDK2 and \\u03b1-tubulin [#10]. Through this proteostatic role CCT8 supports cell cycle progression and cytoskeletal organization [#3, #4] and is required for thymocyte maturation, T cell activation, and protective immunity [#7]. In cancer, CCT8 acts in pro-tumorigenic signaling: it binds LASP1 to exclude wild-type p53 from the nucleus and promote EMT [#6], interacts with and activates AKT to drive migration and metastasis [#8], and functions downstream of GRP94 in a c-Jun/EMT cascade [#5]. CCT8 also serves as a host factor for influenza A replication via interaction with the viral PB2 protein [#11].\"\n  ,\n  \"teleology\": [\n    {\n      \"year\": 1995,\n      \"claim\": \"Established CCT8 as a bona fide subunit of the cytosolic chaperonin rather than a free-standing protein, defining its molecular identity.\",\n      \"evidence\": \"cDNA cloning, sequence motif analysis, and 2D gel analysis of the native CCT complex\",\n      \"pmids\": [\"7890169\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"ATPase activity inferred from motifs, not directly measured\", \"subunit stoichiometry and arrangement within the complex not resolved\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Answered how CCT8 expression is controlled, linking chaperonin subunit levels to mitogenic Ras/MAPK signaling through specific TCF transcription factors.\",\n      \"evidence\": \"Reporter assays, EMSA, MAPK inhibitor, and dominant-negative TCF constructs on the promoter\",\n      \"pmids\": [\"12788937\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"downstream physiological consequences of TCF-driven CCT8 induction not tested\", \"whether other CCT subunits are co-regulated unknown\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Demonstrated that CCT8 is rate-limiting for TRiC/CCT assembly and that boosting it has functional proteostatic consequences, reframing a single subunit as a lever on whole-complex activity.\",\n      \"evidence\": \"Ectopic CCT8 overexpression, native assembly assays, mutant Huntingtin aggregation readout, and TRiC-dependent C. elegans lifespan extension\",\n      \"pmids\": [\"27892468\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"structural basis for how excess CCT8 nucleates assembly not defined\", \"client spectrum protected by elevated TRiC not enumerated\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Connected CCT8 loss to a defined cell-cycle phenotype, implicating chaperonin function in S-phase entry.\",\n      \"evidence\": \"siRNA knockdown with proliferation assays and flow cytometry in hepatocellular carcinoma cells\",\n      \"pmids\": [\"24862099\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"client(s) responsible for S-phase block not identified at this stage\", \"single cell line\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Extended CCT8's cellular role to cytoskeletal organization and invasion, and positioned it within a GRP94-driven metastatic cascade.\",\n      \"evidence\": \"siRNA/shRNA knockdown, invasion and migration assays, cytoskeleton imaging, and western blot for c-Jun/EMT markers in glioblastoma and HCC cells\",\n      \"pmids\": [\"26304164\", \"26718209\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"direct biochemical link between CCT8 and GRP94 not shown\", \"molecular mechanism connecting CCT8 to c-Jun unresolved\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Identified specific physical partners (LASP1) and a signaling output, showing CCT8 controls p53 subcellular localization to drive EMT.\",\n      \"evidence\": \"Co-immunoprecipitation, nuclear fractionation/immunofluorescence for p53, functional assays, and clinical tissue correlation\",\n      \"pmids\": [\"34862361\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"mechanism by which the CCT8-LASP1 interaction excludes p53 not defined\", \"whether p53 is a folding client unknown\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Established the physiological requirement for CCT chaperonin in adaptive immunity, linking proteostasis to T cell development, activation, and protective responses.\",\n      \"evidence\": \"Conditional CCT8 knockout in mice, proteomics, nuclear actin imaging, activation assays, and in vivo helminth infection\",\n      \"pmids\": [\"34083746\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"which T-cell client proteins are misfolded upon CCT loss not fully mapped\", \"mechanism of aberrant Th2 polarization not resolved\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Placed CCT8 upstream of AKT in a pro-metastatic signaling axis, expanding its tumorigenic function beyond folding.\",\n      \"evidence\": \"Co-immunoprecipitation, overexpression/knockdown, AKT inhibitor rescue, and in vivo metastasis model in lung adenocarcinoma\",\n      \"pmids\": [\"37928427\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"whether AKT activation is direct or chaperone-mediated unclear\", \"structural detail of CCT8-AKT interaction absent\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Defined a specific folding client (TULP2) engaged through the CCT8 apical domain, linking CCT8 to ciliogenesis and male fertility.\",\n      \"evidence\": \"Co-IP domain mapping, knockdown aggregation assay, IFT localization in KO mice, and a human TULP2 infertility variant\",\n      \"pmids\": [\"40613306\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"ATP-dependence of TULP2 folding cycle not shown\", \"whole-complex vs CCT8-specific contribution to TULP2 folding unresolved\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Revealed crosstalk between Hsp90 and chaperonin systems by showing CCT8 itself is an FKBP4-Hsp90 client whose stability gates downstream clients.\",\n      \"evidence\": \"BioID proximity labeling, FKBP4 knockdown, CCT8 aggregation assay, and client stability blots (CDK2, \\u03b1-tubulin)\",\n      \"pmids\": [\"41203126\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"whether FKBP4-Hsp90 acts on free CCT8 or assembled complex unknown\", \"generality across CCT subunits untested\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Identified CCT8 as a host dependency factor for influenza A through interaction with viral PB2.\",\n      \"evidence\": \"Co-immunoprecipitation and knockdown/overexpression with viral titer readouts\",\n      \"pmids\": [\"40135264\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"whether PB2 is folded by CCT8 or merely bound unclear\", \"single viral subtype tested\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Proposed a CCT8-RPL4 interaction feeding into MDM2-p53 control of p53 degradation in colorectal cancer.\",\n      \"evidence\": \"Co-immunoprecipitation plus functional assays and bioinformatic network analysis\",\n      \"pmids\": [\"40251552\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"p53 ubiquitination/degradation mechanism inferred from correlation, not directly demonstrated\", \"RPL4 interaction not reciprocally validated\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How CCT8-specific client selection and apical-domain recognition relate to whole-complex TRiC folding cycles, and how its many signaling outputs (AKT, p53, EMT) emerge mechanistically from chaperonin function, remain unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"no structural model of CCT8 client engagement within the assembled complex\", \"distinction between folding-dependent and folding-independent signaling roles not drawn\", \"comprehensive client repertoire undefined\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0044183\", \"supporting_discovery_ids\": [0, 2, 9, 10]},\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [9, 10]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [0, 9]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [2, 9, 10]},\n      {\"term_id\": \"R-HSA-1640170\", \"supporting_discovery_ids\": [3, 6]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [7]}\n    ],\n    \"complexes\": [\n      \"TRiC/CCT chaperonin complex\"\n    ],\n    \"partners\": [\n      \"LASP1\",\n      \"AKT\",\n      \"TULP2\",\n      \"FKBP4\",\n      \"RPL4\",\n      \"PB2 (influenza A)\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":7,"faith_pct":100.0}}