{"gene":"CCT2","run_date":"2026-06-09T22:57:17","timeline":{"discoveries":[{"year":2022,"finding":"CCT2 functions as an autophagy receptor (aggrephagy receptor) for solid protein aggregates by associating with aggregation-prone proteins independent of ubiquitination and interacting with autophagosome marker ATG8s through a non-classical VLIR motif. Aggregation-prone protein accumulation induces a functional switch of CCT2 from a chaperonin subunit to an autophagy receptor by promoting CCT2 monomer formation, which exposes the VLIR motif for ATG8 interaction.","method":"Co-immunoprecipitation, in vitro binding assays, mutagenesis of VLIR motif, live-cell imaging, mouse brain model, comparison with ubiquitin-binding receptors P62/NBR1/TAX1BP1","journal":"Cell","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — multiple orthogonal methods (Co-IP, mutagenesis, in vivo model), mechanistic dissection of the VLIR motif and monomer formation in a single rigorous study","pmids":["35366418"],"is_preprint":false},{"year":2022,"finding":"CCT2-mediated aggrephagy specifically promotes autophagic degradation of solid protein aggregates (low liquidity) but not liquid condensates, and operates independently of the ubiquitin-binding receptors P62, NBR1, and TAX1BP1, and independently of chaperone-mediated autophagy.","method":"Genetic knockdown/knockout with phenotypic readout comparing aggregate vs. condensate clearance; comparison with other receptor mutants","journal":"Cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — clearly defined loss-of-function phenotype with multiple controls distinguishing aggregate types and pathway independence, in single rigorous study","pmids":["35366418"],"is_preprint":false},{"year":2024,"finding":"Atg1 (ULK1 ortholog) phosphorylates CCT2 at Ser412 and Ser470; disruption of these phosphorylation sites impairs solid aggrephagy by hindering CCT2-Atg8 binding. Additionally, adaptor protein Atg11 directly associates with CCT2 through its CC4 domain, and this interaction is required for CCT2-Atg8 binding and efficient aggrephagy. Both mechanisms are conserved in mammalian cells.","method":"In vitro kinase assay, phosphosite mutagenesis, Co-IP, domain mapping, yeast and mammalian cell assays","journal":"EMBO reports","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — phosphorylation mapped by kinase assay and mutagenesis, Atg11 interaction mapped by domain truncation, conservation confirmed in mammalian cells","pmids":["39322741"],"is_preprint":false},{"year":2023,"finding":"The LCA-associated double mutation T400P/R516H in CCT2 (corresponding to T394P/R510H in yeast) reduces the off-rate of ADP during ATP hydrolysis by the CCT/TRiC complex, stabilizing its closed state and thereby impeding the exit of CCT2 monomers from the complex required for autophagy function. ATPase activity of CCT/TRiC is stimulated by non-folded substrate.","method":"Steady-state and transient kinetic analysis of ATPase activity in yeast CCT/TRiC with disease-mimicking mutations","journal":"Communications biology","confidence":"High","confidence_rationale":"Tier 1 / Moderate — rigorous biochemical kinetic analysis with mutant and wild-type comparison, single lab but in vitro enzymatic assay with mechanistic interpretation","pmids":["37644231"],"is_preprint":false},{"year":2016,"finding":"LCA-causative mutations T400P and R516H in CCT2 destabilize the chaperonin complex and impair affinity for adjacent subunit CCTγ. CCT2 knockdown reduces the major client protein transducin β1 (Gβ1), and wild-type but not mutant CCT2 rescues proliferation defects in Cct2-knockdown cells.","method":"Biochemical stability assays, Co-IP for subunit interactions, Cct2 knockdown in 661W cells with rescue by wild-type vs. mutant expression, patient-derived iPSCs","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal interaction assay plus functional rescue experiment, single lab, two orthogonal methods","pmids":["27645772"],"is_preprint":false},{"year":2018,"finding":"In zebrafish, loss of cct2 (L394H-7del CRISPR mutation) leads to reduced levels of client protein Gβ1, attenuated retinal ganglion cell differentiation, disrupted cell cycle, and increased retinal cell death. Injection of wild-type human CCTβ RNA rescues the small eye phenotype and restores Gβ1 levels, confirming CCT2's role in folding Gβ1 and retinal development.","method":"CRISPR-Cas9 knockout zebrafish, immunostaining, TUNEL, EdU assay, RNA rescue injection, western blot for client protein","journal":"Investigative ophthalmology & visual science","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic model with phenotypic rescue and biochemical client protein readout, multiple orthogonal assays in single rigorous study","pmids":["29450543"],"is_preprint":false},{"year":2024,"finding":"CCT2 directly binds to KRAS (shown by co-immunoprecipitation, mass spectrometry, and surface plasmon resonance), leading to increased KRAS protein stability and upregulated downstream KRAS signaling in glioblastoma. Dihydroartemisinin directly binds CCT2 and reduces KRAS expression; CCT2 overexpression rescues the inhibitory effect of dihydroartemisinin on glioblastoma.","method":"Co-immunoprecipitation, mass spectrometry, surface plasmon resonance, overexpression rescue assay, in vivo glioblastoma animal model","journal":"Cancer letters","confidence":"Medium","confidence_rationale":"Tier 1-2 / Moderate — direct binding confirmed by three methods including SPR, functional rescue experiment, single lab","pmids":["38582394"],"is_preprint":false},{"year":2019,"finding":"Under hypoxia, CCT2 interacts with Gli-1 (a Hedgehog signaling transcription factor) as identified by mass spectrometry. CCT2 depletion inhibits tumor induction by Gli-1, and CCT2 assists in Gli-1 folding to prevent ubiquitination-mediated Gli-1 degradation by β-TrCP in colorectal cancer cells.","method":"Mass spectrometry, western blotting, immunofluorescence, siRNA knockdown, xenograft model","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — interaction identified by MS and confirmed functionally, but direct folding assay not reported; multiple cellular assays in single lab","pmids":["31462707"],"is_preprint":false},{"year":2019,"finding":"CCT2 (and CCT5) are required for stabilization of Cdc20, and depletion of CCT2 reduces Cdc20 levels and reverses Muscovy duck reovirus p10.8-mediated CDK4 degradation and apoptosis, placing CCT2 upstream of Cdc20 in cell cycle and apoptosis regulation.","method":"siRNA knockdown, western blot, apoptosis assay, cell cycle analysis","journal":"Veterinary microbiology","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — epistasis established by knockdown with specific downstream readout (Cdc20 levels, CDK4 degradation), single lab, single method","pmids":["31282373"],"is_preprint":false},{"year":2024,"finding":"PRRSV nsp3 enhances the interaction between porcine MDA5 and CCT2, promoting aggregate formation and autophagic clearance of MDA5-CCT2-nsp3 complexes independently of ubiquitination, thereby suppressing innate immune signaling.","method":"Co-immunoprecipitation, autophagy flux assays, siRNA knockdown, western blot","journal":"Virologica Sinica","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — Co-IP confirms interaction, functional autophagy assays support mechanism, single lab","pmids":["38272236"],"is_preprint":false},{"year":2024,"finding":"Lassa virus matrix protein Z interacts with CCT2 (via residues Q29 and Y48 on LASV-Z), blocking actin and tubulin folding, disrupting the cytoskeleton, and preventing autophagosome-lysosome fusion, leading to autophagosome accumulation that promotes viral particle budding.","method":"Co-immunoprecipitation, site-directed mutagenesis, fluorescence microscopy for autophagosome-lysosome fusion, VLP budding assay","journal":"Autophagy","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — interaction mapped by mutagenesis and Co-IP, functional consequence tested in VLP assay, single lab","pmids":["39007910"],"is_preprint":false},{"year":2024,"finding":"E3 ubiquitin ligase Trim21 facilitates CCT2 ubiquitination and degradation, reversing CCT2's pro-tumorigenic effects in breast cancer. CCT2 promotes breast cancer growth and metastasis through activation of the JAK2/STAT3 signaling pathway. Exosomal CCT2 from breast cancer cells suppresses CD4+ T cell activation by constraining Ca2+-NFAT1 signaling and reducing CD40L expression.","method":"Co-immunoprecipitation, ubiquitination assay, knockdown/overexpression with downstream signaling readout (JAK2/STAT3 phosphorylation), exosome isolation and T cell co-culture assay","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — ubiquitination assay plus downstream signaling readout plus exosome functional assay, single lab, multiple methods","pmids":["39079960"],"is_preprint":false},{"year":2020,"finding":"CCT2 enriched in UC-MSC-derived extracellular vesicles regulates calcium channels to affect Ca2+ influx, suppressing CD154 (CD40L) synthesis in CD4+ T cells via the Ca2+-calcineurin-NFAT1 signaling pathway, thereby modulating the inflammatory response in liver ischemia/reperfusion injury.","method":"Protein mass spectrometry of EV contents, Ca2+ flux measurement, western blot for NFAT1/calcineurin pathway components, in vivo mouse liver IRI model","journal":"Advanced science","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — MS identification plus downstream pathway assays, in vivo validation, single lab","pmids":["32999825"],"is_preprint":false},{"year":2024,"finding":"CCT2 prevents β-catenin proteasomal degradation in epithelial ovarian cancer by recruiting the HSP105-PP2A dephosphorylation complex to β-catenin via direct physical interaction, preventing phosphorylation-induced proteasomal degradation and causing intracellular accumulation of active β-catenin and increased Wnt signaling.","method":"Co-IP assays, ubiquitin assays, western blot for β-catenin phosphorylation, knockdown/overexpression with Wnt target readout","journal":"Molecular biology reports","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — Co-IP maps the ternary complex, ubiquitination assay confirms stabilization, single lab","pmids":["38165547"],"is_preprint":false},{"year":2024,"finding":"CCT2 is required for ciliogenesis: knockdown of CCT2 reduces the number of ciliated cells and results in shorter primary cilia. CCT2, as part of a TRiC/CCT-BBS chaperonin co-complex, is required for the localization of the adhesion GPCR ADGRV1 to the base of primary cilia; in the absence of CCT2, ADGRV1 is depleted from the ciliary base and degraded via the proteasome.","method":"siRNA knockdown with ciliogenesis phenotyping, immunofluorescence localization, co-complex pulldown, proteasome inhibitor rescue assay","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — localization tied to functional consequence (ciliogenesis defect and substrate degradation), preprint with multiple methods, single lab","pmids":["bio_10.1101_2024.10.31.621306"],"is_preprint":true},{"year":2025,"finding":"CCT2 recruits TRIM28 to catalyze SUMO2 modification of TMX1, inhibiting TMX1 ubiquitination and enhancing TMX1 protein stability, which promotes TMX1-dependent ROS clearance and confers resistance to third-generation EGFR-TKIs in non-small cell lung cancer.","method":"CRISPR/Cas9 genome-wide screen, TMT proteomic analysis, Co-IP, SUMOylation and ubiquitination assays, ROS measurement, xenograft models","journal":"Cell death and differentiation","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — interaction and PTM confirmed by Co-IP and ubiquitination/SUMOylation assays, functional rescue in vivo, single lab","pmids":["41168408"],"is_preprint":false},{"year":2026,"finding":"CCT2 directly interacts with and stabilizes the glycolytic enzyme ALDOA (aldolase A) in hepatocellular carcinoma, as shown by co-immunoprecipitation and GST pulldown, resulting in increased glycolytic activity (extracellular acidification rate, glucose uptake, lactate production).","method":"Co-immunoprecipitation, GST pulldown, extracellular acidification rate measurement, glucose uptake and lactate assays, metabolomic profiling","journal":"International journal of biological sciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct binding confirmed by two methods (Co-IP and GST pulldown), functional metabolic readout, single lab","pmids":["42003909"],"is_preprint":false},{"year":2026,"finding":"CCT2 transcription is upregulated by transcription factor FOXA1; CCT2 interacts with EIF3F and FASN to form a ternary CCT2/EIF3F/FASN complex that enhances EIF3F-mediated deubiquitination of FASN, increasing FASN protein stability and lipid synthesis in prostate cancer.","method":"ChIP for FOXA1-CCT2 promoter binding, Co-IP for ternary complex, ubiquitination assay for FASN, lipid synthesis assays, in vivo xenograft and PDX models","journal":"Advanced science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ternary complex mapped by Co-IP, ubiquitination assay confirms mechanism, in vivo validation, single lab","pmids":["42231807"],"is_preprint":false},{"year":2026,"finding":"CCT2 facilitates autophagy-mediated turnover of DNA-bound cGAS aggregates (cGAS-DNA condensates), thereby attenuating cGAS-STING innate immune signaling. CCT2 was identified as a cGAS-associated factor using site-specific photo-cross-linking coupled with quantitative proteomics.","method":"Residue-resolved photo-cross-linking, quantitative proteomics, autophagy flux assays, cGAS-STING reporter assays","journal":"ACS chemical biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — novel photo-cross-linking method identifies interaction, functional autophagy and immune signaling assays confirm role, single lab","pmids":["42043443"],"is_preprint":false},{"year":2024,"finding":"In a mouse model, the CCT2 R516H homozygous mutation causes photoreceptor degeneration with significant depletion of TRiC/CCT substrate proteins in the retina, while T400P homozygosity causes embryonic lethality. CCDC181 was identified as an interacting protein for CCTβ, and its localization to photoreceptor connecting cilia is compromised in the compound heterozygous T400P/R516H mutant mouse.","method":"Knock-in mouse model, retinal histology, western blot for substrate proteins, Co-IP for CCDC181 interaction, immunofluorescence for ciliary localization","journal":"Communications biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo genetic model with substrate depletion and new interactor identified, single lab","pmids":["38830954"],"is_preprint":false}],"current_model":"CCT2 is a dual-function protein: as part of the TRiC/CCT chaperonin ring complex it folds client proteins (including Gβ1, KRAS, ALDOA, actin, tubulin, and FASN via ternary complexes) in an ATP-dependent manner, and upon accumulation of solid protein aggregates it undergoes monomer formation that exposes a VLIR motif, switching its function to serve as a ubiquitination-independent aggrephagy receptor that binds ATG8s (regulated by Atg1-mediated phosphorylation at Ser412/Ser470 and by Atg11 interaction) to deliver solid aggregates for autophagic clearance; additionally, CCT2 participates in ciliogenesis, regulates immune signaling (cGAS-STING, Ca2+-NFAT1, JAK2/STAT3 pathways), and is itself subject to ubiquitin-mediated degradation by TRIM21 and SUMO2 modification by the CCT2-TRIM28 axis."},"narrative":{"mechanistic_narrative":"CCT2 (CCTβ) is a subunit of the TRiC/CCT chaperonin that folds an array of client proteins in an ATP-dependent manner and, under conditions of protein aggregation, converts into a dedicated autophagy receptor, giving it a central role in cellular proteostasis [PMID:35366418, PMID:29450543]. As a chaperonin subunit it folds and stabilizes clients including transducin Gβ1, whose levels collapse upon CCT2 loss in retinal models [PMID:27645772, PMID:29450543], and its ATPase cycle is stimulated by non-folded substrate [PMID:37644231]. Upon accumulation of solid (low-liquidity) protein aggregates, CCT2 monomer formation exposes a non-canonical VLIR motif that binds ATG8 family proteins, allowing CCT2 to deliver solid aggregates for autophagic clearance independently of ubiquitin and of the receptors P62, NBR1, and TAX1BP1 [PMID:35366418]. This aggrephagy function is gated by Atg1/ULK1-mediated phosphorylation at Ser412 and Ser470 and by direct association with the adaptor Atg11, both required for CCT2–ATG8 binding [PMID:39322741]. Disease-causing T400P/R516H mutations stabilize the closed, ADP-bound chaperonin state and impede release of CCT2 monomers, linking chaperonin kinetics to the autophagy switch [PMID:37644231]; in mice these mutations deplete TRiC substrates and cause photoreceptor degeneration, establishing CCT2 in inherited retinal degeneration (Leber congenital amaurosis) [PMID:38830954, PMID:27645772]. CCT2 also supports ciliogenesis, acting with a TRiC-BBS co-complex to localize the adhesion GPCR ADGRV1 to the ciliary base and prevent its proteasomal degradation [PMID:bio_10.1101_2024.10.31.621306]. Across cancers, CCT2 binds and stabilizes oncogenic and metabolic clients — KRAS, β-catenin, ALDOA, and a CCT2/EIF3F/FASN ternary complex — and shapes immune signaling through cGAS-STING aggregate turnover and Ca2+-NFAT1 modulation [PMID:38582394, PMID:38165547, PMID:42003909, PMID:42231807, PMID:42043443, PMID:32999825]. CCT2 protein abundance is itself controlled by TRIM21-mediated ubiquitination, and CCT2 recruits TRIM28 to drive SUMO2 modification of client substrates [PMID:39079960, PMID:41168408].","teleology":[{"year":2016,"claim":"Establishing that CCT2 disease mutations act through the chaperonin connected an inherited retinal disease to TRiC client folding, defining CCT2's first disease-relevant mechanism.","evidence":"biochemical stability and Co-IP assays plus knockdown/rescue in 661W cells and patient iPSCs for the T400P/R516H mutations","pmids":["27645772"],"confidence":"Medium","gaps":["did not resolve whether mutant defects arise from folding loss or autophagy loss","no structural model of the mutant complex"]},{"year":2018,"claim":"An in vivo genetic model showed CCT2 is required to fold the client Gβ1 and to support retinal development, moving the disease link from cell lines to organismal phenotype.","evidence":"CRISPR cct2 knockout zebrafish with TUNEL, EdU, immunostaining, and human CCT2 RNA rescue restoring Gβ1","pmids":["29450543"],"confidence":"High","gaps":["did not test which other clients contribute to the eye phenotype","mechanism of cell-cycle disruption left open"]},{"year":2022,"claim":"Discovery of the moonlighting switch — CCT2 monomers exposing a VLIR motif to act as a ubiquitin-independent aggrephagy receptor — redefined CCT2 beyond a folding subunit and explained selective clearance of solid aggregates.","evidence":"Co-IP, in vitro binding, VLIR mutagenesis, live-cell imaging, mouse brain model, and comparison against P62/NBR1/TAX1BP1","pmids":["35366418"],"confidence":"High","gaps":["trigger that initiates monomerization in vivo not fully defined","structural basis of monomer-state VLIR exposure not resolved"]},{"year":2023,"claim":"Kinetic analysis linked the LCA mutations to a slowed ADP off-rate and stabilized closed state, mechanistically tying chaperonin ATPase behavior to the inability to release CCT2 monomers for autophagy.","evidence":"steady-state and transient ATPase kinetics on yeast CCT/TRiC bearing disease-mimicking mutations","pmids":["37644231"],"confidence":"High","gaps":["performed in yeast complex, not human","did not directly measure monomer exit rates"]},{"year":2024,"claim":"Identification of Atg1/ULK1 phosphorylation at Ser412/Ser470 and Atg11 binding established the regulatory inputs controlling the aggrephagy switch and confirmed conservation to mammals.","evidence":"in vitro kinase assay, phosphosite mutagenesis, domain-mapped Co-IP in yeast and mammalian cells","pmids":["39322741"],"confidence":"High","gaps":["phosphatase that reverses the marks unknown","how phosphorylation alters monomer/oligomer equilibrium not shown"]},{"year":2024,"claim":"A knock-in mouse confirmed allele-specific severity (R516H photoreceptor degeneration vs T400P embryonic lethality) and identified CCDC181 as a ciliary CCTβ interactor, extending CCT2 function to connecting-cilium biology.","evidence":"knock-in mouse retinal histology, substrate western blots, Co-IP, and ciliary immunofluorescence","pmids":["38830954"],"confidence":"Medium","gaps":["folding vs autophagy contribution to retinal loss not separated","CCDC181 functional dependence on CCT2 untested"]},{"year":2024,"claim":"Multiple studies established CCT2 as a stabilizer of oncogenic clients (KRAS, β-catenin) and a regulator of cancer signaling and immune evasion, broadening its client repertoire beyond folding housekeeping.","evidence":"Co-IP/MS/SPR for KRAS, ternary HSP105-PP2A-β-catenin Co-IP, JAK2/STAT3 readouts, TRIM21 ubiquitination, and exosomal Ca2+-NFAT1 T-cell assays","pmids":["38582394","38165547","39079960"],"confidence":"Medium","gaps":["whether stabilization reflects direct chaperonin folding versus scaffolding unresolved","single-lab results per client"]},{"year":2024,"claim":"CCT2 was shown to be exploited by viruses (PRRSV, Lassa, MDA5 pathway) and to govern ciliogenesis via TRiC-BBS-mediated ADGRV1 localization, mapping its dual chaperone/autophagy roles onto immune and ciliary contexts.","evidence":"Co-IP, mutagenesis, autophagy flux, VLP budding assays, and ciliogenesis phenotyping with proteasome rescue (one preprint)","pmids":["38272236","39007910","31462707","31282373"],"confidence":"Medium","gaps":["ciliary findings are from a preprint","physiological relevance of viral hijacking beyond cell models unclear"]},{"year":2026,"claim":"Recent work extended CCT2 to metabolic and innate-immune control, stabilizing ALDOA and a FASN-containing complex to drive glycolysis/lipogenesis and clearing cGAS-DNA condensates to dampen STING signaling.","evidence":"Co-IP/GST pulldown with metabolic flux assays, FOXA1 ChIP and CCT2/EIF3F/FASN Co-IP, photo-cross-linking proteomics and cGAS-STING reporters","pmids":["42003909","42231807","42043443"],"confidence":"Medium","gaps":["each mechanism rests on a single study","whether these depend on chaperonin folding or aggrephagy not dissected"]},{"year":null,"claim":"It remains unresolved how the cell quantitatively partitions CCT2 between its chaperonin folding role and its monomeric aggrephagy-receptor role, and what governs this balance across tissues and disease states.","evidence":"","pmids":[],"confidence":"Medium","gaps":["no in vivo measurement of the monomer/complex ratio under stress","structural determinants of the switch not solved","tissue-specific regulation unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140657","term_label":"ATP-dependent activity","supporting_discovery_ids":[3]},{"term_id":"GO:0044183","term_label":"protein folding chaperone","supporting_discovery_ids":[0,4,5]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[0,1]},{"term_id":"GO:0008092","term_label":"cytoskeletal protein binding","supporting_discovery_ids":[10]}],"localization":[{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[0,6]},{"term_id":"GO:0005929","term_label":"cilium","supporting_discovery_ids":[14,19]}],"pathway":[{"term_id":"R-HSA-9612973","term_label":"Autophagy","supporting_discovery_ids":[0,1,2,9,18]},{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[4,5,6]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[9,11,12,18]},{"term_id":"R-HSA-1852241","term_label":"Organelle biogenesis and maintenance","supporting_discovery_ids":[14]}],"complexes":["TRiC/CCT chaperonin","TRiC-BBS co-complex","CCT2/EIF3F/FASN complex"],"partners":["ATG8","ATG11","KRAS","CCT3","ADGRV1","TRIM21","TRIM28","EIF3F"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"P78371","full_name":"T-complex protein 1 subunit beta","aliases":["CCT-beta","Chaperonin containing T-complex polypeptide 1 subunit 2"],"length_aa":535,"mass_kda":57.5,"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","url":"https://www.uniprot.org/uniprotkb/P78371/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":true,"resolved_as":"","url":"https://depmap.org/portal/gene/CCT2","classification":"Common Essential","n_dependent_lines":1205,"n_total_lines":1208,"dependency_fraction":0.9975165562913907},"opencell":{"profiled":true,"resolved_as":"","ensg_id":"ENSG00000166226","cell_line_id":"CID000207","localizations":[{"compartment":"cytoplasmic","grade":3},{"compartment":"nucleoplasm","grade":3}],"interactors":[{"gene":"ACTB","stoichiometry":10.0},{"gene":"CCT7","stoichiometry":10.0},{"gene":"TCP1","stoichiometry":10.0},{"gene":"CCT8","stoichiometry":10.0},{"gene":"CCT4","stoichiometry":10.0},{"gene":"CCT6A","stoichiometry":10.0},{"gene":"CCT5","stoichiometry":10.0},{"gene":"CCT3","stoichiometry":10.0},{"gene":"PDCD5","stoichiometry":10.0},{"gene":"PPP2CA","stoichiometry":10.0}],"url":"https://opencell.sf.czbiohub.org/target/CID000207","total_profiled":1310},"omim":[{"mim_id":"618608","title":"INTELLECTUAL DEVELOPMENTAL DISORDER WITH NASAL SPEECH, DYSMORPHIC FACIES, AND VARIABLE SKELETAL ANOMALIES; IDNADFS","url":"https://www.omim.org/entry/618608"},{"mim_id":"616768","title":"TUBULIN, BETA-8; TUBB8","url":"https://www.omim.org/entry/616768"},{"mim_id":"610150","title":"CHAPERONIN CONTAINING T-COMPLEX POLYPEPTIDE 1, SUBUNIT 5; CCT5","url":"https://www.omim.org/entry/610150"},{"mim_id":"605142","title":"CHAPERONIN CONTAINING T-COMPLEX POLYPEPTIDE 1, SUBUNIT 4; CCT4","url":"https://www.omim.org/entry/605142"},{"mim_id":"605140","title":"CHAPERONIN CONTAINING T-COMPLEX POLYPEPTIDE 1, SUBUNIT 7; CCT7","url":"https://www.omim.org/entry/605140"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Cytosol","reliability":"Supported"},{"location":"Connecting piece","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/CCT2"},"hgnc":{"alias_symbol":["Cctb"],"prev_symbol":[]},"alphafold":{"accession":"P78371","domains":[{"cath_id":"1.10.560.10","chopping":"16-146_408-452_497-521","consensus_level":"high","plddt":92.7507,"start":16,"end":521},{"cath_id":"3.50.7.10","chopping":"218-367","consensus_level":"high","plddt":88.0416,"start":218,"end":367}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P78371","model_url":"https://alphafold.ebi.ac.uk/files/AF-P78371-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P78371-F1-predicted_aligned_error_v6.png","plddt_mean":89.81},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=CCT2","jax_strain_url":"https://www.jax.org/strain/search?query=CCT2"},"sequence":{"accession":"P78371","fasta_url":"https://rest.uniprot.org/uniprotkb/P78371.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P78371/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P78371"}},"corpus_meta":[{"pmid":"35366418","id":"PMC_35366418","title":"CCT2 is an aggrephagy receptor for clearance of solid protein aggregates.","date":"2022","source":"Cell","url":"https://pubmed.ncbi.nlm.nih.gov/35366418","citation_count":146,"is_preprint":false},{"pmid":"32999825","id":"PMC_32999825","title":"Extracellular Vesicles Derived from Human Umbilical Cord Mesenchymal Stem Cells Protect Liver Ischemia/Reperfusion Injury by Reducing CD154 Expression on CD4+ T Cells via CCT2.","date":"2020","source":"Advanced science (Weinheim, Baden-Wurttemberg, Germany)","url":"https://pubmed.ncbi.nlm.nih.gov/32999825","citation_count":105,"is_preprint":false},{"pmid":"25704758","id":"PMC_25704758","title":"Two members of the TRiC chaperonin complex, CCT2 and TCP1 are essential for survival of breast cancer cells and are linked to driving oncogenes.","date":"2015","source":"Experimental cell research","url":"https://pubmed.ncbi.nlm.nih.gov/25704758","citation_count":86,"is_preprint":false},{"pmid":"31462707","id":"PMC_31462707","title":"Activating CCT2 triggers Gli-1 activation during hypoxic condition in colorectal cancer.","date":"2019","source":"Oncogene","url":"https://pubmed.ncbi.nlm.nih.gov/31462707","citation_count":39,"is_preprint":false},{"pmid":"27645772","id":"PMC_27645772","title":"CCT2 Mutations Evoke Leber Congenital Amaurosis due to Chaperone Complex Instability.","date":"2016","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/27645772","citation_count":37,"is_preprint":false},{"pmid":"23782473","id":"PMC_23782473","title":"Clinicopathological features and CCT2 and PDIA2 expression in gallbladder squamous/adenosquamous carcinoma and gallbladder adenocarcinoma.","date":"2013","source":"World journal of surgical oncology","url":"https://pubmed.ncbi.nlm.nih.gov/23782473","citation_count":31,"is_preprint":false},{"pmid":"31282373","id":"PMC_31282373","title":"Cdc20 and molecular chaperone CCT2 and CCT5 are required for the Muscovy duck reovirus p10.8-induced cell cycle arrest and 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biology","url":"https://pubmed.ncbi.nlm.nih.gov/37644231","citation_count":6,"is_preprint":false},{"pmid":"39007910","id":"PMC_39007910","title":"Lassa virus Z protein hijacks the autophagy machinery for efficient transportation by interrupting CCT2-mediated cytoskeleton network formation.","date":"2024","source":"Autophagy","url":"https://pubmed.ncbi.nlm.nih.gov/39007910","citation_count":5,"is_preprint":false},{"pmid":"38165547","id":"PMC_38165547","title":"CCT2 prevented β-catenin proteasomal degradation to sustain cancer stem cell traits and promote tumor progression in epithelial ovarian cancer.","date":"2024","source":"Molecular biology reports","url":"https://pubmed.ncbi.nlm.nih.gov/38165547","citation_count":5,"is_preprint":false},{"pmid":"37561257","id":"PMC_37561257","title":"Tat-CCT2 Protects the Neurons from Ischemic Damage by Reducing Oxidative Stress and Activating Autophagic Removal of Damaged Protein in the Gerbil Hippocampus.","date":"2023","source":"Neurochemical 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Regulates ZEB1-Induced EMT Gene Transcription to Promote the Metastasis and Tumorigenesis of Papillary Thyroid Carcinoma.","date":"2024","source":"Discovery medicine","url":"https://pubmed.ncbi.nlm.nih.gov/39327245","citation_count":2,"is_preprint":false},{"pmid":"39614031","id":"PMC_39614031","title":"Neuroprotective Effects of Chaperonin Containing TCP1 Subunit 2 (CCT2) on Motor Neurons Following Oxidative or Ischemic Stress.","date":"2024","source":"Neurochemical research","url":"https://pubmed.ncbi.nlm.nih.gov/39614031","citation_count":2,"is_preprint":false},{"pmid":"40374738","id":"PMC_40374738","title":"Clinical characterization of CCT2 and its role in autophagy regulation during age-related macular degeneration.","date":"2025","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/40374738","citation_count":1,"is_preprint":false},{"pmid":"41288742","id":"PMC_41288742","title":"Histone lactylation drives METTL3 upregulation-mediated RNA m6A modification of CCT2 to 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Macrophage Polarization in HCC tumorigenesis.","date":"2026","source":"International journal of biological sciences","url":"https://pubmed.ncbi.nlm.nih.gov/42003909","citation_count":0,"is_preprint":false},{"pmid":"42098225","id":"PMC_42098225","title":"CCT2 regulates the proliferation, apoptosis, and cell cycle arrest of multiple myeloma cells through the P53 signalling pathway.","date":"2026","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/42098225","citation_count":0,"is_preprint":false},{"pmid":"42043443","id":"PMC_42043443","title":"Site-Specific Photo-Cross-Linking Reveals CCT2 as a Regulator of cGAS-STING Signaling via Clearance of cGAS-DNA Condensates.","date":"2026","source":"ACS chemical biology","url":"https://pubmed.ncbi.nlm.nih.gov/42043443","citation_count":0,"is_preprint":false},{"pmid":"41789667","id":"PMC_41789667","title":"Knockdown of CCT2 inhibits the malignant progression of hepatocellular carcinoma cells by impairing STAT3 activation.","date":"2026","source":"Oncology reports","url":"https://pubmed.ncbi.nlm.nih.gov/41789667","citation_count":0,"is_preprint":false},{"pmid":"42231807","id":"PMC_42231807","title":"CCT2 Promotes Prostate Cancer Progression Through EIF3F-Dependent Stabilization of FASN.","date":"2026","source":"Advanced science (Weinheim, Baden-Wurttemberg, Germany)","url":"https://pubmed.ncbi.nlm.nih.gov/42231807","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2024.10.31.621306","title":"The BBS/CCT chaperonin complex ensures the localization of the adhesion G protein-coupled receptor ADGRV1 to primary cilia","date":"2024-11-03","source":"bioRxiv","url":"https://doi.org/10.1101/2024.10.31.621306","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":19879,"output_tokens":5162,"usd":0.068533,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":13482,"output_tokens":3794,"usd":0.08113,"stage2_stop_reason":"end_turn"},"total_usd":0.149663,"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\": 2022,\n      \"finding\": \"CCT2 functions as an autophagy receptor (aggrephagy receptor) for solid protein aggregates by associating with aggregation-prone proteins independent of ubiquitination and interacting with autophagosome marker ATG8s through a non-classical VLIR motif. Aggregation-prone protein accumulation induces a functional switch of CCT2 from a chaperonin subunit to an autophagy receptor by promoting CCT2 monomer formation, which exposes the VLIR motif for ATG8 interaction.\",\n      \"method\": \"Co-immunoprecipitation, in vitro binding assays, mutagenesis of VLIR motif, live-cell imaging, mouse brain model, comparison with ubiquitin-binding receptors P62/NBR1/TAX1BP1\",\n      \"journal\": \"Cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — multiple orthogonal methods (Co-IP, mutagenesis, in vivo model), mechanistic dissection of the VLIR motif and monomer formation in a single rigorous study\",\n      \"pmids\": [\"35366418\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"CCT2-mediated aggrephagy specifically promotes autophagic degradation of solid protein aggregates (low liquidity) but not liquid condensates, and operates independently of the ubiquitin-binding receptors P62, NBR1, and TAX1BP1, and independently of chaperone-mediated autophagy.\",\n      \"method\": \"Genetic knockdown/knockout with phenotypic readout comparing aggregate vs. condensate clearance; comparison with other receptor mutants\",\n      \"journal\": \"Cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — clearly defined loss-of-function phenotype with multiple controls distinguishing aggregate types and pathway independence, in single rigorous study\",\n      \"pmids\": [\"35366418\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Atg1 (ULK1 ortholog) phosphorylates CCT2 at Ser412 and Ser470; disruption of these phosphorylation sites impairs solid aggrephagy by hindering CCT2-Atg8 binding. Additionally, adaptor protein Atg11 directly associates with CCT2 through its CC4 domain, and this interaction is required for CCT2-Atg8 binding and efficient aggrephagy. Both mechanisms are conserved in mammalian cells.\",\n      \"method\": \"In vitro kinase assay, phosphosite mutagenesis, Co-IP, domain mapping, yeast and mammalian cell assays\",\n      \"journal\": \"EMBO reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — phosphorylation mapped by kinase assay and mutagenesis, Atg11 interaction mapped by domain truncation, conservation confirmed in mammalian cells\",\n      \"pmids\": [\"39322741\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"The LCA-associated double mutation T400P/R516H in CCT2 (corresponding to T394P/R510H in yeast) reduces the off-rate of ADP during ATP hydrolysis by the CCT/TRiC complex, stabilizing its closed state and thereby impeding the exit of CCT2 monomers from the complex required for autophagy function. ATPase activity of CCT/TRiC is stimulated by non-folded substrate.\",\n      \"method\": \"Steady-state and transient kinetic analysis of ATPase activity in yeast CCT/TRiC with disease-mimicking mutations\",\n      \"journal\": \"Communications biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — rigorous biochemical kinetic analysis with mutant and wild-type comparison, single lab but in vitro enzymatic assay with mechanistic interpretation\",\n      \"pmids\": [\"37644231\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"LCA-causative mutations T400P and R516H in CCT2 destabilize the chaperonin complex and impair affinity for adjacent subunit CCTγ. CCT2 knockdown reduces the major client protein transducin β1 (Gβ1), and wild-type but not mutant CCT2 rescues proliferation defects in Cct2-knockdown cells.\",\n      \"method\": \"Biochemical stability assays, Co-IP for subunit interactions, Cct2 knockdown in 661W cells with rescue by wild-type vs. mutant expression, patient-derived iPSCs\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal interaction assay plus functional rescue experiment, single lab, two orthogonal methods\",\n      \"pmids\": [\"27645772\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"In zebrafish, loss of cct2 (L394H-7del CRISPR mutation) leads to reduced levels of client protein Gβ1, attenuated retinal ganglion cell differentiation, disrupted cell cycle, and increased retinal cell death. Injection of wild-type human CCTβ RNA rescues the small eye phenotype and restores Gβ1 levels, confirming CCT2's role in folding Gβ1 and retinal development.\",\n      \"method\": \"CRISPR-Cas9 knockout zebrafish, immunostaining, TUNEL, EdU assay, RNA rescue injection, western blot for client protein\",\n      \"journal\": \"Investigative ophthalmology & visual science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic model with phenotypic rescue and biochemical client protein readout, multiple orthogonal assays in single rigorous study\",\n      \"pmids\": [\"29450543\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"CCT2 directly binds to KRAS (shown by co-immunoprecipitation, mass spectrometry, and surface plasmon resonance), leading to increased KRAS protein stability and upregulated downstream KRAS signaling in glioblastoma. Dihydroartemisinin directly binds CCT2 and reduces KRAS expression; CCT2 overexpression rescues the inhibitory effect of dihydroartemisinin on glioblastoma.\",\n      \"method\": \"Co-immunoprecipitation, mass spectrometry, surface plasmon resonance, overexpression rescue assay, in vivo glioblastoma animal model\",\n      \"journal\": \"Cancer letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — direct binding confirmed by three methods including SPR, functional rescue experiment, single lab\",\n      \"pmids\": [\"38582394\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Under hypoxia, CCT2 interacts with Gli-1 (a Hedgehog signaling transcription factor) as identified by mass spectrometry. CCT2 depletion inhibits tumor induction by Gli-1, and CCT2 assists in Gli-1 folding to prevent ubiquitination-mediated Gli-1 degradation by β-TrCP in colorectal cancer cells.\",\n      \"method\": \"Mass spectrometry, western blotting, immunofluorescence, siRNA knockdown, xenograft model\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — interaction identified by MS and confirmed functionally, but direct folding assay not reported; multiple cellular assays in single lab\",\n      \"pmids\": [\"31462707\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"CCT2 (and CCT5) are required for stabilization of Cdc20, and depletion of CCT2 reduces Cdc20 levels and reverses Muscovy duck reovirus p10.8-mediated CDK4 degradation and apoptosis, placing CCT2 upstream of Cdc20 in cell cycle and apoptosis regulation.\",\n      \"method\": \"siRNA knockdown, western blot, apoptosis assay, cell cycle analysis\",\n      \"journal\": \"Veterinary microbiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — epistasis established by knockdown with specific downstream readout (Cdc20 levels, CDK4 degradation), single lab, single method\",\n      \"pmids\": [\"31282373\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"PRRSV nsp3 enhances the interaction between porcine MDA5 and CCT2, promoting aggregate formation and autophagic clearance of MDA5-CCT2-nsp3 complexes independently of ubiquitination, thereby suppressing innate immune signaling.\",\n      \"method\": \"Co-immunoprecipitation, autophagy flux assays, siRNA knockdown, western blot\",\n      \"journal\": \"Virologica Sinica\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — Co-IP confirms interaction, functional autophagy assays support mechanism, single lab\",\n      \"pmids\": [\"38272236\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Lassa virus matrix protein Z interacts with CCT2 (via residues Q29 and Y48 on LASV-Z), blocking actin and tubulin folding, disrupting the cytoskeleton, and preventing autophagosome-lysosome fusion, leading to autophagosome accumulation that promotes viral particle budding.\",\n      \"method\": \"Co-immunoprecipitation, site-directed mutagenesis, fluorescence microscopy for autophagosome-lysosome fusion, VLP budding assay\",\n      \"journal\": \"Autophagy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — interaction mapped by mutagenesis and Co-IP, functional consequence tested in VLP assay, single lab\",\n      \"pmids\": [\"39007910\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"E3 ubiquitin ligase Trim21 facilitates CCT2 ubiquitination and degradation, reversing CCT2's pro-tumorigenic effects in breast cancer. CCT2 promotes breast cancer growth and metastasis through activation of the JAK2/STAT3 signaling pathway. Exosomal CCT2 from breast cancer cells suppresses CD4+ T cell activation by constraining Ca2+-NFAT1 signaling and reducing CD40L expression.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay, knockdown/overexpression with downstream signaling readout (JAK2/STAT3 phosphorylation), exosome isolation and T cell co-culture assay\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — ubiquitination assay plus downstream signaling readout plus exosome functional assay, single lab, multiple methods\",\n      \"pmids\": [\"39079960\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"CCT2 enriched in UC-MSC-derived extracellular vesicles regulates calcium channels to affect Ca2+ influx, suppressing CD154 (CD40L) synthesis in CD4+ T cells via the Ca2+-calcineurin-NFAT1 signaling pathway, thereby modulating the inflammatory response in liver ischemia/reperfusion injury.\",\n      \"method\": \"Protein mass spectrometry of EV contents, Ca2+ flux measurement, western blot for NFAT1/calcineurin pathway components, in vivo mouse liver IRI model\",\n      \"journal\": \"Advanced science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — MS identification plus downstream pathway assays, in vivo validation, single lab\",\n      \"pmids\": [\"32999825\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"CCT2 prevents β-catenin proteasomal degradation in epithelial ovarian cancer by recruiting the HSP105-PP2A dephosphorylation complex to β-catenin via direct physical interaction, preventing phosphorylation-induced proteasomal degradation and causing intracellular accumulation of active β-catenin and increased Wnt signaling.\",\n      \"method\": \"Co-IP assays, ubiquitin assays, western blot for β-catenin phosphorylation, knockdown/overexpression with Wnt target readout\",\n      \"journal\": \"Molecular biology reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — Co-IP maps the ternary complex, ubiquitination assay confirms stabilization, single lab\",\n      \"pmids\": [\"38165547\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"CCT2 is required for ciliogenesis: knockdown of CCT2 reduces the number of ciliated cells and results in shorter primary cilia. CCT2, as part of a TRiC/CCT-BBS chaperonin co-complex, is required for the localization of the adhesion GPCR ADGRV1 to the base of primary cilia; in the absence of CCT2, ADGRV1 is depleted from the ciliary base and degraded via the proteasome.\",\n      \"method\": \"siRNA knockdown with ciliogenesis phenotyping, immunofluorescence localization, co-complex pulldown, proteasome inhibitor rescue assay\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — localization tied to functional consequence (ciliogenesis defect and substrate degradation), preprint with multiple methods, single lab\",\n      \"pmids\": [\"bio_10.1101_2024.10.31.621306\"],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"CCT2 recruits TRIM28 to catalyze SUMO2 modification of TMX1, inhibiting TMX1 ubiquitination and enhancing TMX1 protein stability, which promotes TMX1-dependent ROS clearance and confers resistance to third-generation EGFR-TKIs in non-small cell lung cancer.\",\n      \"method\": \"CRISPR/Cas9 genome-wide screen, TMT proteomic analysis, Co-IP, SUMOylation and ubiquitination assays, ROS measurement, xenograft models\",\n      \"journal\": \"Cell death and differentiation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — interaction and PTM confirmed by Co-IP and ubiquitination/SUMOylation assays, functional rescue in vivo, single lab\",\n      \"pmids\": [\"41168408\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"CCT2 directly interacts with and stabilizes the glycolytic enzyme ALDOA (aldolase A) in hepatocellular carcinoma, as shown by co-immunoprecipitation and GST pulldown, resulting in increased glycolytic activity (extracellular acidification rate, glucose uptake, lactate production).\",\n      \"method\": \"Co-immunoprecipitation, GST pulldown, extracellular acidification rate measurement, glucose uptake and lactate assays, metabolomic profiling\",\n      \"journal\": \"International journal of biological sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct binding confirmed by two methods (Co-IP and GST pulldown), functional metabolic readout, single lab\",\n      \"pmids\": [\"42003909\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"CCT2 transcription is upregulated by transcription factor FOXA1; CCT2 interacts with EIF3F and FASN to form a ternary CCT2/EIF3F/FASN complex that enhances EIF3F-mediated deubiquitination of FASN, increasing FASN protein stability and lipid synthesis in prostate cancer.\",\n      \"method\": \"ChIP for FOXA1-CCT2 promoter binding, Co-IP for ternary complex, ubiquitination assay for FASN, lipid synthesis assays, in vivo xenograft and PDX models\",\n      \"journal\": \"Advanced science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ternary complex mapped by Co-IP, ubiquitination assay confirms mechanism, in vivo validation, single lab\",\n      \"pmids\": [\"42231807\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"CCT2 facilitates autophagy-mediated turnover of DNA-bound cGAS aggregates (cGAS-DNA condensates), thereby attenuating cGAS-STING innate immune signaling. CCT2 was identified as a cGAS-associated factor using site-specific photo-cross-linking coupled with quantitative proteomics.\",\n      \"method\": \"Residue-resolved photo-cross-linking, quantitative proteomics, autophagy flux assays, cGAS-STING reporter assays\",\n      \"journal\": \"ACS chemical biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — novel photo-cross-linking method identifies interaction, functional autophagy and immune signaling assays confirm role, single lab\",\n      \"pmids\": [\"42043443\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"In a mouse model, the CCT2 R516H homozygous mutation causes photoreceptor degeneration with significant depletion of TRiC/CCT substrate proteins in the retina, while T400P homozygosity causes embryonic lethality. CCDC181 was identified as an interacting protein for CCTβ, and its localization to photoreceptor connecting cilia is compromised in the compound heterozygous T400P/R516H mutant mouse.\",\n      \"method\": \"Knock-in mouse model, retinal histology, western blot for substrate proteins, Co-IP for CCDC181 interaction, immunofluorescence for ciliary localization\",\n      \"journal\": \"Communications biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo genetic model with substrate depletion and new interactor identified, single lab\",\n      \"pmids\": [\"38830954\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"CCT2 is a dual-function protein: as part of the TRiC/CCT chaperonin ring complex it folds client proteins (including Gβ1, KRAS, ALDOA, actin, tubulin, and FASN via ternary complexes) in an ATP-dependent manner, and upon accumulation of solid protein aggregates it undergoes monomer formation that exposes a VLIR motif, switching its function to serve as a ubiquitination-independent aggrephagy receptor that binds ATG8s (regulated by Atg1-mediated phosphorylation at Ser412/Ser470 and by Atg11 interaction) to deliver solid aggregates for autophagic clearance; additionally, CCT2 participates in ciliogenesis, regulates immune signaling (cGAS-STING, Ca2+-NFAT1, JAK2/STAT3 pathways), and is itself subject to ubiquitin-mediated degradation by TRIM21 and SUMO2 modification by the CCT2-TRIM28 axis.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"CCT2 (CCTβ) is a subunit of the TRiC/CCT chaperonin that folds an array of client proteins in an ATP-dependent manner and, under conditions of protein aggregation, converts into a dedicated autophagy receptor, giving it a central role in cellular proteostasis [#0, #5]. As a chaperonin subunit it folds and stabilizes clients including transducin Gβ1, whose levels collapse upon CCT2 loss in retinal models [#4, #5], and its ATPase cycle is stimulated by non-folded substrate [#3]. Upon accumulation of solid (low-liquidity) protein aggregates, CCT2 monomer formation exposes a non-canonical VLIR motif that binds ATG8 family proteins, allowing CCT2 to deliver solid aggregates for autophagic clearance independently of ubiquitin and of the receptors P62, NBR1, and TAX1BP1 [#0, #1]. This aggrephagy function is gated by Atg1/ULK1-mediated phosphorylation at Ser412 and Ser470 and by direct association with the adaptor Atg11, both required for CCT2–ATG8 binding [#2]. Disease-causing T400P/R516H mutations stabilize the closed, ADP-bound chaperonin state and impede release of CCT2 monomers, linking chaperonin kinetics to the autophagy switch [#3]; in mice these mutations deplete TRiC substrates and cause photoreceptor degeneration, establishing CCT2 in inherited retinal degeneration (Leber congenital amaurosis) [#19, #4]. CCT2 also supports ciliogenesis, acting with a TRiC-BBS co-complex to localize the adhesion GPCR ADGRV1 to the ciliary base and prevent its proteasomal degradation [#14]. Across cancers, CCT2 binds and stabilizes oncogenic and metabolic clients — KRAS, β-catenin, ALDOA, and a CCT2/EIF3F/FASN ternary complex — and shapes immune signaling through cGAS-STING aggregate turnover and Ca2+-NFAT1 modulation [#6, #13, #16, #17, #18, #12]. CCT2 protein abundance is itself controlled by TRIM21-mediated ubiquitination, and CCT2 recruits TRIM28 to drive SUMO2 modification of client substrates [#11, #15].\"\n,\n  \"teleology\": [\n    {\n      \"year\": 2016,\n      \"claim\": \"Establishing that CCT2 disease mutations act through the chaperonin connected an inherited retinal disease to TRiC client folding, defining CCT2's first disease-relevant mechanism.\",\n      \"evidence\": \"biochemical stability and Co-IP assays plus knockdown/rescue in 661W cells and patient iPSCs for the T400P/R516H mutations\",\n      \"pmids\": [\"27645772\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"did not resolve whether mutant defects arise from folding loss or autophagy loss\", \"no structural model of the mutant complex\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"An in vivo genetic model showed CCT2 is required to fold the client Gβ1 and to support retinal development, moving the disease link from cell lines to organismal phenotype.\",\n      \"evidence\": \"CRISPR cct2 knockout zebrafish with TUNEL, EdU, immunostaining, and human CCT2 RNA rescue restoring Gβ1\",\n      \"pmids\": [\"29450543\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"did not test which other clients contribute to the eye phenotype\", \"mechanism of cell-cycle disruption left open\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Discovery of the moonlighting switch — CCT2 monomers exposing a VLIR motif to act as a ubiquitin-independent aggrephagy receptor — redefined CCT2 beyond a folding subunit and explained selective clearance of solid aggregates.\",\n      \"evidence\": \"Co-IP, in vitro binding, VLIR mutagenesis, live-cell imaging, mouse brain model, and comparison against P62/NBR1/TAX1BP1\",\n      \"pmids\": [\"35366418\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"trigger that initiates monomerization in vivo not fully defined\", \"structural basis of monomer-state VLIR exposure not resolved\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Kinetic analysis linked the LCA mutations to a slowed ADP off-rate and stabilized closed state, mechanistically tying chaperonin ATPase behavior to the inability to release CCT2 monomers for autophagy.\",\n      \"evidence\": \"steady-state and transient ATPase kinetics on yeast CCT/TRiC bearing disease-mimicking mutations\",\n      \"pmids\": [\"37644231\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"performed in yeast complex, not human\", \"did not directly measure monomer exit rates\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Identification of Atg1/ULK1 phosphorylation at Ser412/Ser470 and Atg11 binding established the regulatory inputs controlling the aggrephagy switch and confirmed conservation to mammals.\",\n      \"evidence\": \"in vitro kinase assay, phosphosite mutagenesis, domain-mapped Co-IP in yeast and mammalian cells\",\n      \"pmids\": [\"39322741\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"phosphatase that reverses the marks unknown\", \"how phosphorylation alters monomer/oligomer equilibrium not shown\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"A knock-in mouse confirmed allele-specific severity (R516H photoreceptor degeneration vs T400P embryonic lethality) and identified CCDC181 as a ciliary CCTβ interactor, extending CCT2 function to connecting-cilium biology.\",\n      \"evidence\": \"knock-in mouse retinal histology, substrate western blots, Co-IP, and ciliary immunofluorescence\",\n      \"pmids\": [\"38830954\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"folding vs autophagy contribution to retinal loss not separated\", \"CCDC181 functional dependence on CCT2 untested\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Multiple studies established CCT2 as a stabilizer of oncogenic clients (KRAS, β-catenin) and a regulator of cancer signaling and immune evasion, broadening its client repertoire beyond folding housekeeping.\",\n      \"evidence\": \"Co-IP/MS/SPR for KRAS, ternary HSP105-PP2A-β-catenin Co-IP, JAK2/STAT3 readouts, TRIM21 ubiquitination, and exosomal Ca2+-NFAT1 T-cell assays\",\n      \"pmids\": [\"38582394\", \"38165547\", \"39079960\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"whether stabilization reflects direct chaperonin folding versus scaffolding unresolved\", \"single-lab results per client\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"CCT2 was shown to be exploited by viruses (PRRSV, Lassa, MDA5 pathway) and to govern ciliogenesis via TRiC-BBS-mediated ADGRV1 localization, mapping its dual chaperone/autophagy roles onto immune and ciliary contexts.\",\n      \"evidence\": \"Co-IP, mutagenesis, autophagy flux, VLP budding assays, and ciliogenesis phenotyping with proteasome rescue (one preprint)\",\n      \"pmids\": [\"38272236\", \"39007910\", \"31462707\", \"31282373\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"ciliary findings are from a preprint\", \"physiological relevance of viral hijacking beyond cell models unclear\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Recent work extended CCT2 to metabolic and innate-immune control, stabilizing ALDOA and a FASN-containing complex to drive glycolysis/lipogenesis and clearing cGAS-DNA condensates to dampen STING signaling.\",\n      \"evidence\": \"Co-IP/GST pulldown with metabolic flux assays, FOXA1 ChIP and CCT2/EIF3F/FASN Co-IP, photo-cross-linking proteomics and cGAS-STING reporters\",\n      \"pmids\": [\"42003909\", \"42231807\", \"42043443\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"each mechanism rests on a single study\", \"whether these depend on chaperonin folding or aggrephagy not dissected\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"It remains unresolved how the cell quantitatively partitions CCT2 between its chaperonin folding role and its monomeric aggrephagy-receptor role, and what governs this balance across tissues and disease states.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"no in vivo measurement of the monomer/complex ratio under stress\", \"structural determinants of the switch not solved\", \"tissue-specific regulation unknown\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140657\", \"supporting_discovery_ids\": [3]},\n      {\"term_id\": \"GO:0044183\", \"supporting_discovery_ids\": [0, 4, 5]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [0, 1]},\n      {\"term_id\": \"GO:0008092\", \"supporting_discovery_ids\": [10]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [0, 6]},\n      {\"term_id\": \"GO:0005929\", \"supporting_discovery_ids\": [14, 19]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-9612973\", \"supporting_discovery_ids\": [0, 1, 2, 9, 18]},\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [4, 5, 6]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [9, 11, 12, 18]},\n      {\"term_id\": \"R-HSA-1852241\", \"supporting_discovery_ids\": [14]}\n    ],\n    \"complexes\": [\"TRiC/CCT chaperonin\", \"TRiC-BBS co-complex\", \"CCT2/EIF3F/FASN complex\"],\n    \"partners\": [\"ATG8\", \"ATG11\", \"KRAS\", \"CCT3\", \"ADGRV1\", \"TRIM21\", \"TRIM28\", \"EIF3F\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":7,"faith_pct":100.0}}