{"gene":"CCT2","run_date":"2026-04-28T17:28:52","timeline":{"discoveries":[{"year":2022,"finding":"CCT2 functions as an aggrephagy receptor that binds aggregation-prone proteins independent of cargo ubiquitination and interacts with autophagosome marker ATG8s through a non-classical VLIR motif. Unlike ubiquitin-binding receptors (P62, NBR1, TAX1BP1), CCT2 specifically promotes autophagic degradation of solid protein aggregates with little liquidity. Accumulation of aggregation-prone proteins induces a functional switch of CCT2 from a chaperone subunit to an autophagy receptor by promoting CCT2 monomer formation, which exposes the VLIR motif for ATG8 interaction.","method":"Co-IP, pulldown, live-cell imaging, loss-of-function experiments in cells and mouse brain, domain mutagenesis (VLIR motif), fractionation assays distinguishing solid vs. liquid aggregates","journal":"Cell","confidence":"High","confidence_rationale":"Tier 1–2 — multiple orthogonal methods, mechanistic rescue experiments, in vivo mouse brain model, replicated in commentary (PMID:35699934)","pmids":["35366418"],"is_preprint":false},{"year":2020,"finding":"CCT2 enriched in UC-MSC-derived extracellular vesicles regulates calcium channels to affect Ca2+ influx and suppress CD154 (CD40L) synthesis in CD4+ T cells via the Ca2+-calcineurin-NFAT1 signaling pathway, thereby modulating inflammatory responses during liver ischemia/reperfusion injury.","method":"Protein mass spectrometry identification of CCT2 in EVs, in vivo liver IRI mouse model, mechanistic pathway analysis of Ca2+-calcineurin-NFAT1 signaling, flow cytometry for CD154 expression","journal":"Advanced science","confidence":"Medium","confidence_rationale":"Tier 2–3 — identified by MS, functional in vivo validation, mechanistic pathway placed but Ca2+ channel identity not fully resolved","pmids":["32999825"],"is_preprint":false},{"year":2015,"finding":"CCT2 (along with TCP1) is essential for survival of breast cancer cells; both genes encode subunits of the TRiC chaperonin complex and are recurrently amplified and overexpressed in breast cancer, with TCP1 expression regulated by PI3K signaling downstream of driver oncogene activation.","method":"RNAi-based functional genetic screen, copy number analysis, expression profiling, siRNA knockdown viability assays, PI3K pathway inhibition","journal":"Experimental cell research","confidence":"Medium","confidence_rationale":"Tier 2 — RNAi functional screen with epistasis to PI3K signaling, but mechanistic detail on CCT2 specifically is limited","pmids":["25704758"],"is_preprint":false},{"year":2019,"finding":"CCT2 (T-complex protein 1 subunit beta) interacts with Gli-1 under hypoxic conditions in colorectal cancer cells, facilitating Gli-1 folding and preventing its ubiquitination-mediated degradation by β-TrCP; reduction of CCT2 inhibits Gli-1-driven tumor induction.","method":"Mass spectrometry identification of CCT2-Gli-1 interaction, western blotting, immunofluorescence, RNAi knockdown, in vivo xenograft models","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2–3 — MS-identified interaction with functional validation in vivo, but direct folding assay not performed","pmids":["31462707"],"is_preprint":false},{"year":2016,"finding":"Compound heterozygous mutations T400P and R516H in CCT2 (CCTβ) cause Leber congenital amaurosis (LCA) by destabilizing the chaperonin complex; mutant CCTβ proteins show reduced affinity for adjacent subunit CCTγ, impair proliferation in patient-derived iPSCs, fail to rescue knockdown phenotypes, and reduce the major client protein transducin β1 (Gβ1) in mouse retina where CCTβ and CCTγ are co-expressed in retinal ganglion cells and photoreceptor connecting cilia.","method":"Biochemical stability assays of mutant proteins, co-IP for CCTβ-CCTγ interaction, patient-derived iPSC proliferation assays, rescue experiments in 661W cells, Cct2 knockdown, immunostaining of mouse retina","journal":"Scientific reports","confidence":"High","confidence_rationale":"Tier 1–2 — multiple orthogonal methods including biochemical interaction assays, cellular rescue, and in vivo retinal characterization","pmids":["27645772"],"is_preprint":false},{"year":2018,"finding":"Loss-of-function cct2 mutation (L394H-7del) in zebrafish causes small eye phenotype, attenuated retinal ganglion cell differentiation, disrupted retinal cell cycle, and increased neural retinal cell death; injection of wild-type human CCTβ RNA rescues the phenotype and restores Gβ1 protein levels, confirming CCT2's essential role in retinal development through cell cycle regulation.","method":"CRISPR-Cas9 mutagenesis, microscopy, immunostaining, TUNEL assay, EdU proliferation assay, RNA rescue injection","journal":"Investigative ophthalmology & visual science","confidence":"High","confidence_rationale":"Tier 1–2 — CRISPR loss-of-function with genetic rescue, multiple cellular readouts, ortholog of human CCT2","pmids":["29450543"],"is_preprint":false},{"year":2019,"finding":"CCT2 and CCT5 are required for stabilization of Cdc20, which is necessary for MDRV p10.8-induced CDK4 degradation via the ubiquitin-proteasome pathway and subsequent cell cycle arrest and apoptosis; depletion of CCT2 reduced Cdc20 levels and reversed p10.8-mediated CDK4 degradation and apoptosis.","method":"siRNA depletion of CCT2/CCT5 and Cdc20, western blotting for CDK4/Cdc20 levels, apoptosis assays, cell cycle analysis","journal":"Veterinary microbiology","confidence":"Medium","confidence_rationale":"Tier 2–3 — functional RNAi epistasis linking CCT2 to Cdc20 stability and downstream cell cycle control, but only in viral infection context","pmids":["31282373"],"is_preprint":false},{"year":2023,"finding":"The LCA-causative double mutation T400P/R516H in yeast CCT2 reduces the off-rate of ADP during ATP hydrolysis by CCT/TRiC, stabilizing the closed state of the chaperonin complex; this impedes CCT2 monomer exit from the complex required for its autophagy receptor function. ATPase activity of CCT/TRiC is stimulated by a non-folded substrate.","method":"Steady-state and transient kinetic analysis of ATPase activity in yeast CCT/TRiC carrying equivalent mutations, substrate-stimulated ATPase assays","journal":"Communications biology","confidence":"High","confidence_rationale":"Tier 1 — rigorous in vitro biochemical kinetic analysis with mutant variants directly explaining the LCA mechanistic defect in autophagy function","pmids":["37644231"],"is_preprint":false},{"year":2024,"finding":"CCT2-mediated aggrephagy is regulated by two mechanisms in yeast (conserved in mammals): (1) Atg1 kinase phosphorylates Cct2 at Ser412 and Ser470, and disruption of these sites impairs solid aggrephagy by hindering Cct2-Atg8 binding; (2) Atg11 (selective autophagy adaptor) directly associates with Cct2 through its CC4 domain, and loss of this interaction weakens Cct2-Atg8 association.","method":"Phosphorylation site mutagenesis, in vivo phosphorylation assays, co-IP, domain mapping of Atg11-Cct2 interaction, aggrephagy functional assays, conservation validated in mammalian cells with LC3C","journal":"EMBO reports","confidence":"High","confidence_rationale":"Tier 1–2 — mutagenesis of phosphorylation sites, domain-resolved interaction mapping, functional aggrephagy readouts, conserved in mammalian cells","pmids":["39322741"],"is_preprint":false},{"year":2024,"finding":"E3 ubiquitin ligase Trim21 facilitates CCT2 ubiquitination and proteasomal degradation in breast cancer cells, reversing CCT2's pro-tumorigenic effects. CCT2 promotes cancer progression via JAK2/STAT3 signaling activation. Exosomal CCT2 from breast cancer cells suppresses CD4+ T cell activation by constraining Ca2+-NFAT1 signaling and reducing CD40L (CD154) expression.","method":"Co-IP for Trim21-CCT2 interaction, ubiquitination assay, CCT2 knockdown/overexpression with JAK2/STAT3 pathway readouts, exosome isolation and treatment experiments, Ca2+-NFAT1 signaling analysis","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2–3 — co-IP-confirmed ubiquitination, pathway activation shown by KD/OE with multiple readouts, mechanistic detail on Ca2+ channel not fully resolved","pmids":["39079960"],"is_preprint":false},{"year":2024,"finding":"PRRSV nsp3 enhances the interaction between porcine MDA5 and CCT2, promoting aggregate formation and autophagic clearance of the MDA5-CCT2-nsp3 complex independently of ubiquitination, thereby suppressing innate immune signaling via CCT2's aggrephagy receptor function.","method":"Co-IP for MDA5-CCT2-nsp3 interaction, autophagy flux assays, MDA5 aggregate formation analysis, nsp3 overexpression, PRRSV infection model","journal":"Virologica Sinica","confidence":"Medium","confidence_rationale":"Tier 2–3 — co-IP with functional autophagic clearance assay, but in viral infection context with multiple simultaneous variables","pmids":["38272236"],"is_preprint":false},{"year":2024,"finding":"CCT2 directly binds to KRAS protein (shown by co-IP, mass spectrometry, and surface plasmon resonance), leading to increased KRAS stability and upregulated downstream KRAS signaling in glioblastoma. Dihydroartemisinin directly binds CCT2 and decreases KRAS expression and signaling; CCT2 overexpression rescues the inhibitory effect of dihydroartemisinin.","method":"Co-immunoprecipitation, mass spectrometry, surface plasmon resonance (direct binding measurement), CCT2 overexpression rescue, glioblastoma animal model","journal":"Cancer letters","confidence":"High","confidence_rationale":"Tier 1–2 — three orthogonal binding methods (Co-IP, MS, SPR) with functional rescue and in vivo validation","pmids":["38582394"],"is_preprint":false},{"year":2024,"finding":"LASV matrix protein (LASV-Z) interacts with CCT2 via glutamine-29 and tyrosine-48 residues, hindering actin and tubulin folding; cytoskeleton disruption caused by this interaction blocks lysosomal enzyme transit and autophagosome-lysosome fusion, promoting autophagosome accumulation that facilitates LASV-like particle budding. Mutation of the LASV-Z interaction sites reduces CCT2 binding and restores autophagic flux.","method":"Co-IP, site-directed mutagenesis of LASV-Z interaction residues, autophagy flux assays (LC3/LAMP1 co-localization), cytoskeleton disruption analysis, VLP budding assay","journal":"Autophagy","confidence":"Medium","confidence_rationale":"Tier 2 — co-IP with mutagenesis validation and functional autophagic flux readout, links CCT2 cytoskeletal folding function to viral life cycle","pmids":["39007910"],"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 with increased Wnt signaling.","method":"Co-IP for CCT2-β-catenin and CCT2-HSP105-PP2A interactions, ubiquitination assay, CCT2 KD/OE with Wnt pathway readouts, cancer stem cell functional assays","journal":"Molecular biology reports","confidence":"Medium","confidence_rationale":"Tier 2–3 — co-IP-confirmed three-way complex, dephosphorylation mechanism proposed with functional pathway readouts","pmids":["38165547"],"is_preprint":false},{"year":2024,"finding":"CCT2 is identified as a critical mediator of acquired resistance to third-generation EGFR-TKIs in lung cancer; mechanistically, CCT2 recruits TRIM28 to catalyze SUMO2 modification of TMX1, inhibiting its ubiquitination and enhancing TMX1 protein stability, which promotes TMX1-dependent ROS clearance conferring drug resistance.","method":"CRISPR/Cas9 genome-wide screen, TMT proteomics, co-IP for CCT2-TRIM28-TMX1 complex, SUMO2 modification assay, ubiquitination assay, ROS measurement, xenograft models","journal":"Cell death and differentiation","confidence":"Medium","confidence_rationale":"Tier 2 — genome-wide CRISPR screen with proteomic validation and co-IP-confirmed PTM mechanism, in vivo xenograft validation","pmids":["41168408"],"is_preprint":false},{"year":2024,"finding":"CCT2 knockdown reduces STAT3 phosphorylation and impairs HCC cell proliferation, migration, invasion, and stemness in vitro and in vivo; IL-6 treatment rescues phosphorylated STAT3 levels and counteracts CCT2 knockdown effects, placing CCT2 upstream of STAT3 activation in hepatocellular carcinoma.","method":"siRNA knockdown, EdU/colony formation/Transwell assays, flow cytometry, xenograft and hematogenous metastasis models, western blotting for p-STAT3, IL-6 rescue experiment","journal":"Oncology reports","confidence":"Medium","confidence_rationale":"Tier 2–3 — clean KD with defined phenotypic readout, epistasis established by IL-6 rescue, but direct CCT2-STAT3 interaction not shown","pmids":["41789667"],"is_preprint":false},{"year":2024,"finding":"Compound heterozygous Cct2 mutations (T400P/R516H) in mice cause aberrant cone cell lamination and early lethality; R516H homozygosity causes photoreceptor degeneration with significant depletion of TRiC/CCT substrate proteins in retina. CCDC181 is identified as a CCTβ-interacting protein whose localization to photoreceptor connecting cilia is compromised in mutant mice.","method":"Generation of knock-in mouse models, histology, immunostaining, retinal phenotyping, co-IP for CCTβ-CCDC181 interaction, localization analysis of ciliary proteins","journal":"Communications biology","confidence":"High","confidence_rationale":"Tier 1–2 — mammalian genetic model with phenotypic characterization, new substrate/interactor (CCDC181) identified by co-IP with in vivo localization validation","pmids":["38830954"],"is_preprint":false},{"year":2026,"finding":"CCT2 directly interacts with and stabilizes the glycolytic enzyme ALDOA, as shown by co-immunoprecipitation and GST pulldown, increasing extracellular acidification rate, glucose uptake, and lactate production in HCC cells. CCT2 also promotes M2 macrophage polarization through exosome-mediated mechanisms, creating an immunosuppressive tumor microenvironment; CCT2 knockdown enhances anti-tumor efficacy of PD-1 blockade in mouse models.","method":"Co-immunoprecipitation, GST pulldown assay, extracellular acidification rate measurement, glucose uptake assay, lactate quantification, metabolomics, THP1 co-culture assay, exosome treatment, in vivo xenograft with PD-1 blockade","journal":"International journal of biological sciences","confidence":"Medium","confidence_rationale":"Tier 1–2 — direct interaction confirmed by two binding assays (Co-IP + GST pulldown) with metabolic functional validation and in vivo immune modulation data","pmids":["42003909"],"is_preprint":false},{"year":2026,"finding":"Site-specific photo-cross-linking coupled with quantitative proteomics identified CCT2 as a cGAS-associated factor; CCT2 attenuates cGAS-STING innate immune signaling by facilitating autophagy-mediated turnover of DNA-bound cGAS aggregates, limiting persistence of immunostimulatory cytosolic DNA signals.","method":"Residue-resolved photo-cross-linking, quantitative proteomics, cGAS-STING signaling assays, autophagy flux analysis, CCT2 loss-of-function","journal":"ACS chemical biology","confidence":"Medium","confidence_rationale":"Tier 1–2 — novel photo-cross-linking proteomics method identifies interaction, functional signaling assays validate role, consistent with established CCT2 aggrephagy function","pmids":["42043443"],"is_preprint":false},{"year":2025,"finding":"Histone H3K18 lactylation upregulates METTL3 expression, which enhances CCT2 translation through m6A modification of CCT2 mRNA; elevated CCT2 in turn weakens CD8+ T cell activity by inhibiting Ca2+ influx, thereby mediating immune evasion in gastric cancer.","method":"CHIP for H3K18la at METTL3 locus, RIP assay for METTL3-CCT2 mRNA m6A modification, CCT2 overexpression/knockdown, Ca2+ influx measurement, T cell cytotoxicity assay, flow cytometry, homograft mouse model","journal":"Cellular and molecular life sciences","confidence":"Medium","confidence_rationale":"Tier 2 — RIP assay confirms m6A modification of CCT2 mRNA, functional Ca2+ and T cell readouts, rescue experiments, but CCT2-Ca2+ channel interaction not directly shown","pmids":["41288742"],"is_preprint":false},{"year":2024,"finding":"CCT2 knockdown in primary cilia studies revealed that the TRiC/CCT chaperonin complex (including CCT2 and CCT3) forms a co-complex with BBS chaperonin-like proteins required for the localization of adhesion GPCR ADGRV1 to primary cilia; in the absence of this co-complex, ADGRV1 is depleted from the base of primary cilia and degraded via the proteasome.","method":"siRNA knockdown of CCT2/CCT3/BBS6, ciliogenesis phenotyping (ciliated cell count, cilia length), immunofluorescence localization of ADGRV1, proteasome inhibitor rescue","journal":"bioRxiv","confidence":"Low","confidence_rationale":"Tier 3 — preprint, single-method knockdown with localization readout, no direct CCT2-ADGRV1 interaction demonstrated","pmids":["bio_10.1101_2024.10.31.621306"],"is_preprint":true}],"current_model":"CCT2 is a dual-function protein that acts canonically as a subunit of the TRiC/CCT chaperonin complex (folding substrates including tubulin, actin, Gβ1, KRAS, Gli-1, and ALDOA in an ATP-dependent manner) and, upon accumulation of solid protein aggregates, undergoes monomer formation that exposes a VLIR motif enabling it to switch function to serve as a ubiquitin-independent aggrephagy receptor that binds aggregation-prone solid aggregates and interacts with ATG8/LC3 proteins — a process regulated by Atg1-mediated phosphorylation at Ser412/Ser470 and direct Atg11 binding — while also modulating immune responses through Ca2+-NFAT signaling suppression in T cells and participating in cancer progression via stabilization of oncoproteins (KRAS, β-catenin) and activation of JAK2/STAT3 and Wnt pathways."},"narrative":{"teleology":[{"year":2015,"claim":"Establishing that CCT2, as a TRiC subunit, is essential for cancer cell survival answered whether individual chaperonin subunits are rate-limiting in proliferating cells and linked CCT2 to oncogenic dependency.","evidence":"RNAi functional genetic screen and copy number analysis in breast cancer cell lines","pmids":["25704758"],"confidence":"Medium","gaps":["Specific substrates mediating cancer cell essentiality were not identified","Whether CCT2 essentiality extends beyond breast cancer was untested"]},{"year":2016,"claim":"Discovery that compound heterozygous CCT2 mutations (T400P/R516H) cause Leber congenital amaurosis revealed that TRiC integrity is critical for retinal cell survival and that Gβ1 is a key retinal client protein whose depletion underlies disease pathogenesis.","evidence":"Biochemical stability assays, co-IP for CCTβ–CCTγ interaction, patient iPSC proliferation assays, rescue in 661W cells, immunostaining of mouse retina","pmids":["27645772"],"confidence":"High","gaps":["Photoreceptor-specific versus retinal ganglion cell contributions to disease were unresolved","Whether partial TRiC disruption affects substrates beyond Gβ1 in retina was unknown"]},{"year":2018,"claim":"Genetic validation in zebrafish demonstrated that CCT2 loss of function causes retinal degeneration and impaired cell cycle progression, and human CCTβ RNA rescue confirmed functional conservation across vertebrates.","evidence":"CRISPR-Cas9 cct2 mutagenesis in zebrafish with RNA rescue, TUNEL and EdU assays","pmids":["29450543"],"confidence":"High","gaps":["Which specific cell cycle regulators require CCT2 folding in retinal progenitors was not determined","Mechanism linking CCT2 to cell cycle regulation versus apoptosis not disentangled"]},{"year":2019,"claim":"Identification of Gli-1 as a CCT2 client under hypoxia expanded the repertoire of cancer-relevant substrates, showing CCT2 prevents β-TrCP-mediated ubiquitination and degradation of an oncogenic transcription factor.","evidence":"Mass spectrometry identification of CCT2–Gli-1 interaction, RNAi knockdown, xenograft colorectal cancer model","pmids":["31462707"],"confidence":"Medium","gaps":["Direct in vitro folding assay for Gli-1 by CCT2 was not performed","Whether the interaction requires the intact TRiC complex or CCT2 monomers was unresolved"]},{"year":2019,"claim":"Demonstration that CCT2 stabilizes Cdc20 revealed a link between the TRiC chaperonin and cell cycle checkpoint control, as CCT2 depletion reduced Cdc20 levels and reversed virus-induced CDK4 degradation.","evidence":"siRNA depletion of CCT2/CCT5 with Cdc20 and CDK4 western blotting, apoptosis and cell cycle assays in MDRV-infected cells","pmids":["31282373"],"confidence":"Medium","gaps":["Only tested in viral infection context; unclear if Cdc20 is a TRiC client in uninfected cells","Direct CCT2–Cdc20 physical interaction not shown"]},{"year":2020,"claim":"Finding that extracellular vesicle–delivered CCT2 suppresses CD4⁺ T cell activation through Ca²⁺-calcineurin-NFAT1 signaling established a non-chaperone immunomodulatory role for CCT2 in the extracellular compartment.","evidence":"Mass spectrometry of UC-MSC-derived EVs, liver IRI mouse model, flow cytometry for CD154, Ca²⁺-calcineurin-NFAT1 pathway analysis","pmids":["32999825"],"confidence":"Medium","gaps":["Identity of the calcium channel regulated by CCT2 was not resolved","Whether CCT2 acts as monomer or oligomer in EVs was not determined"]},{"year":2022,"claim":"The landmark discovery that CCT2 functions as a ubiquitin-independent aggrephagy receptor fundamentally redefined CCT2 as a bifunctional protein: aggregate accumulation triggers CCT2 monomer release from TRiC, exposing a VLIR motif for ATG8 binding and selective clearance of solid (not liquid) aggregates.","evidence":"Co-IP, pulldown, live-cell imaging, VLIR motif mutagenesis, fractionation of solid vs. liquid aggregates, loss-of-function in cells and mouse brain","pmids":["35366418"],"confidence":"High","gaps":["The structural basis for the monomer–oligomer switch was not resolved","Whether CCT2 aggrephagy is active in all cell types was not established","Signals triggering monomerization beyond aggregate accumulation were unknown"]},{"year":2023,"claim":"Kinetic analysis of LCA-causative CCT2 mutations revealed that T400P/R516H slows ADP off-rate, stabilizing the closed TRiC state and trapping CCT2 within the complex, thereby explaining how these mutations simultaneously impair both chaperonin cycling and aggrephagy receptor availability.","evidence":"Steady-state and transient kinetic ATPase assays on yeast TRiC carrying equivalent mutations, substrate-stimulated ATPase measurements","pmids":["37644231"],"confidence":"High","gaps":["Whether the kinetic defect affects all TRiC substrates equally or selectively was untested","Structural detail of how mutations alter the ADP binding pocket was not determined"]},{"year":2024,"claim":"Elucidation of the regulatory mechanisms controlling CCT2 aggrephagy showed that Atg1-mediated phosphorylation (Ser412/Ser470) and direct Atg11 binding both promote CCT2–ATG8 interaction, providing the first upstream signaling pathway governing the chaperone-to-receptor switch.","evidence":"Phosphorylation site mutagenesis, in vivo phosphorylation assays, domain mapping of Atg11–Cct2 interaction, aggrephagy assays in yeast and mammalian cells","pmids":["39322741"],"confidence":"High","gaps":["Mammalian kinase equivalent of Atg1 acting on CCT2 confirmed only for conservation, not fully characterized","Whether other post-translational modifications regulate the switch was unknown"]},{"year":2024,"claim":"Multiple studies converged to show CCT2 stabilizes diverse oncoproteins—KRAS via direct binding (confirmed by SPR), β-catenin via recruitment of the HSP105–PP2A dephosphorylation complex—and activates JAK2/STAT3 signaling, establishing CCT2 as a multi-pathway oncogenic chaperone.","evidence":"Co-IP, mass spectrometry, surface plasmon resonance for KRAS binding; co-IP for CCT2–β-catenin–HSP105–PP2A; JAK2/STAT3 pathway readouts with IL-6 rescue; xenograft models","pmids":["38582394","38165547","41789667"],"confidence":"Medium","gaps":["Direct CCT2–STAT3 physical interaction was not demonstrated","Whether β-catenin stabilization requires TRiC or monomeric CCT2 is unknown","Structural basis for CCT2–KRAS interaction not resolved"]},{"year":2024,"claim":"Knock-in mouse models carrying LCA mutations confirmed retinal photoreceptor degeneration and identified CCDC181 as a new CCT2-interacting protein whose ciliary localization depends on functional CCT2, extending the disease mechanism to ciliary proteostasis.","evidence":"Cct2 knock-in mice (T400P/R516H), retinal histology, co-IP for CCTβ–CCDC181, immunostaining of connecting cilia","pmids":["38830954"],"confidence":"High","gaps":["Whether CCDC181 mislocalization is sufficient to cause photoreceptor degeneration was not tested","Full inventory of ciliary substrates affected by CCT2 mutations was not determined"]},{"year":2024,"claim":"Viral exploitation studies revealed that PRRSV nsp3 hijacks CCT2's aggrephagy function to degrade MDA5 aggregates, and LASV matrix protein disrupts CCT2's cytoskeletal folding to block autophagosome–lysosome fusion, demonstrating that pathogens target both arms of CCT2 biology.","evidence":"Co-IP for MDA5–CCT2–nsp3 and LASV-Z–CCT2, mutagenesis of viral interaction sites, autophagy flux assays, VLP budding assays","pmids":["38272236","39007910"],"confidence":"Medium","gaps":["Host factor specificity—whether other TRiC subunits are similarly exploited—was not compared","Relevance to in vivo viral pathogenesis in animal infection models not established"]},{"year":2025,"claim":"Discovery that CCT2 mRNA is m6A-modified by METTL3 downstream of histone lactylation revealed an epitranscriptomic axis controlling CCT2 protein levels in tumors, and elevated CCT2 suppresses CD8⁺ T cell cytotoxicity by inhibiting Ca²⁺ influx.","evidence":"ChIP for H3K18la at METTL3 locus, RIP for m6A on CCT2 mRNA, Ca²⁺ influx measurement, T cell cytotoxicity assay, homograft mouse model","pmids":["41288742"],"confidence":"Medium","gaps":["Direct molecular target of CCT2 that mediates Ca²⁺ channel inhibition remains unidentified","Whether this regulatory axis operates in non-gastric cancers was untested"]},{"year":2026,"claim":"Identification of ALDOA as a direct CCT2 client linked chaperonin function to glycolytic reprogramming, while exosomal CCT2 was shown to polarize macrophages toward the immunosuppressive M2 phenotype, and CCT2 was separately identified as a cGAS-associated factor that attenuates cGAS-STING signaling through aggrephagy-mediated clearance of DNA-bound cGAS aggregates.","evidence":"Co-IP and GST pulldown for CCT2–ALDOA; ECAR, glucose uptake, lactate assays; exosome M2 polarization; photo-cross-linking proteomics for cGAS–CCT2; autophagy flux and STING signaling assays","pmids":["42003909","42043443"],"confidence":"Medium","gaps":["Whether ALDOA folding requires full TRiC or monomeric CCT2 was not resolved","The exosomal CCT2 form (monomer vs. complex) acting on macrophages was not characterized","Whether cGAS aggregate clearance is specific to CCT2 or shared with other aggrephagy receptors was not tested"]},{"year":null,"claim":"Key unresolved questions include the structural basis and signals governing the TRiC-to-monomer transition, the identity of the calcium channel modulated by CCT2 in immune cells, whether CCT2's oncogenic functions require the intact chaperonin or the monomeric form, and the full client repertoire in different tissue contexts.","evidence":"","pmids":[],"confidence":"High","gaps":["Structural basis for monomer release from TRiC not determined","Calcium channel identity downstream of CCT2 in T cells unknown","Systematic TRiC-dependent vs. monomer-dependent substrate classification lacking"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0044183","term_label":"protein folding chaperone","supporting_discovery_ids":[0,3,4,5,11,12,16,17]},{"term_id":"GO:0140657","term_label":"ATP-dependent activity","supporting_discovery_ids":[7]},{"term_id":"GO:0038024","term_label":"cargo receptor activity","supporting_discovery_ids":[0,8,10,18]}],"localization":[{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[0,7,11]},{"term_id":"GO:0005929","term_label":"cilium","supporting_discovery_ids":[4,16]},{"term_id":"GO:0005576","term_label":"extracellular region","supporting_discovery_ids":[1,9,17]}],"pathway":[{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[0,3,4,5,7,11,16,17]},{"term_id":"R-HSA-9612973","term_label":"Autophagy","supporting_discovery_ids":[0,8,10,12,18]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[1,9,10,18,19]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[9,11,13,15]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[4,5,16]}],"complexes":["TRiC/CCT chaperonin complex"],"partners":["CCT5","CCT3","KRAS","ALDOA","CTNNB1","GLI1","CCDC181","TRIM21"],"other_free_text":[]},"mechanistic_narrative":"CCT2 is a subunit of the TRiC/CCT chaperonin complex that folds obligate substrates including tubulin, actin, G-transducin β1, KRAS, Gli-1, and ALDOA in an ATP-dependent manner, and it moonlights as a ubiquitin-independent aggrephagy receptor for solid protein aggregates. When solid aggregates accumulate, CCT2 exits the TRiC complex as a monomer, exposing a non-classical VLIR motif that binds ATG8/LC3 family proteins; this receptor switch is positively regulated by Atg1-mediated phosphorylation at Ser412/Ser470 and by direct Atg11 binding, while LCA-causative mutations (T400P/R516H) impair ADP release and trap CCT2 in the closed complex, blocking both chaperone and aggrephagy functions [PMID:35366418, PMID:39322741, PMID:37644231]. Compound heterozygous CCT2 mutations cause Leber congenital amaurosis through destabilization of the TRiC complex and depletion of retinal client proteins including Gβ1 and CCDC181 at photoreceptor connecting cilia [PMID:27645772, PMID:38830954]. Beyond proteostasis, CCT2 promotes tumor progression by stabilizing oncoproteins such as KRAS and β-catenin, activating JAK2/STAT3 signaling, and suppressing anti-tumor immunity through inhibition of Ca²⁺-NFAT signaling in T cells [PMID:38582394, PMID:38165547, PMID:39079960, PMID:41288742]."},"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":144,"is_preprint":false,"source_track":"pubmed_title"},{"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":103,"is_preprint":false,"source_track":"pubmed_title"},{"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":85,"is_preprint":false,"source_track":"pubmed_title"},{"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":38,"is_preprint":false,"source_track":"pubmed_title"},{"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,"source_track":"pubmed_title"},{"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,"source_track":"pubmed_title"},{"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 apoptosis.","date":"2019","source":"Veterinary microbiology","url":"https://pubmed.ncbi.nlm.nih.gov/31282373","citation_count":29,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"29450543","id":"PMC_29450543","title":"Mutation in the Zebrafish cct2 Gene Leads to Abnormalities of Cell Cycle and Cell Death in the Retina: A Model of CCT2-Related Leber Congenital Amaurosis.","date":"2018","source":"Investigative ophthalmology & visual science","url":"https://pubmed.ncbi.nlm.nih.gov/29450543","citation_count":23,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"39079960","id":"PMC_39079960","title":"Trim21-mediated CCT2 ubiquitination suppresses malignant progression and promotes CD4+T cell activation in breast cancer.","date":"2024","source":"Cell death & disease","url":"https://pubmed.ncbi.nlm.nih.gov/39079960","citation_count":21,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"38272236","id":"PMC_38272236","title":"PRRSV degrades MDA5 via dual autophagy receptors P62 and CCT2 to evade antiviral innate immunity.","date":"2024","source":"Virologica Sinica","url":"https://pubmed.ncbi.nlm.nih.gov/38272236","citation_count":20,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"35429902","id":"PMC_35429902","title":"TSPAN31 regulates the proliferation, migration, and apoptosis of gastric cancer cells through the METTL1/CCT2 pathway.","date":"2022","source":"Translational oncology","url":"https://pubmed.ncbi.nlm.nih.gov/35429902","citation_count":20,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"35699934","id":"PMC_35699934","title":"CCT2, a newly identified aggrephagy receptor in mammals, specifically mediates the autophagic clearance of solid protein aggregates.","date":"2022","source":"Autophagy","url":"https://pubmed.ncbi.nlm.nih.gov/35699934","citation_count":17,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"37866478","id":"PMC_37866478","title":"Circ-CCT2 Activates Wnt/β-catenin Signaling to Facilitate Hepatoblastoma Development by Stabilizing PTBP1 mRNA.","date":"2023","source":"Cellular and molecular gastroenterology and hepatology","url":"https://pubmed.ncbi.nlm.nih.gov/37866478","citation_count":12,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"36704351","id":"PMC_36704351","title":"Multi-omics analysis revealed the role of CCT2 in the induction of autophagy in Alzheimer's disease.","date":"2023","source":"Frontiers in genetics","url":"https://pubmed.ncbi.nlm.nih.gov/36704351","citation_count":9,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"38582394","id":"PMC_38582394","title":"Targeting the molecular chaperone CCT2 inhibits GBM progression by influencing KRAS stability.","date":"2024","source":"Cancer letters","url":"https://pubmed.ncbi.nlm.nih.gov/38582394","citation_count":7,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"37644231","id":"PMC_37644231","title":"Reduced ADP off-rate by the yeast CCT2 double mutation T394P/R510H which causes Leber congenital amaurosis in humans.","date":"2023","source":"Communications biology","url":"https://pubmed.ncbi.nlm.nih.gov/37644231","citation_count":6,"is_preprint":false,"source_track":"pubmed_title"},{"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,"source_track":"pubmed_title"},{"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,"source_track":"pubmed_title"},{"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 research","url":"https://pubmed.ncbi.nlm.nih.gov/37561257","citation_count":5,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"39478698","id":"PMC_39478698","title":"The essential role of CCT2 in the regulation of aggrephagy.","date":"2024","source":"Frontiers in aging neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/39478698","citation_count":4,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"39322741","id":"PMC_39322741","title":"Two distinct regulatory pathways govern Cct2-Atg8 binding in the process of solid aggrephagy.","date":"2024","source":"EMBO reports","url":"https://pubmed.ncbi.nlm.nih.gov/39322741","citation_count":3,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"38830954","id":"PMC_38830954","title":"Compound heterozygous mutations in a mouse model of Leber congenital amaurosis reveal the role of CCT2 in photoreceptor maintenance.","date":"2024","source":"Communications biology","url":"https://pubmed.ncbi.nlm.nih.gov/38830954","citation_count":3,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"39327245","id":"PMC_39327245","title":"CCT2 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,"source_track":"pubmed_title"},{"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,"source_track":"pubmed_title"},{"pmid":"41288742","id":"PMC_41288742","title":"Histone lactylation drives METTL3 upregulation-mediated RNA m6A modification of CCT2 to hinder CD8+ T cell survival in gastric cancer.","date":"2025","source":"Cellular and molecular life sciences : CMLS","url":"https://pubmed.ncbi.nlm.nih.gov/41288742","citation_count":0,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"41261179","id":"PMC_41261179","title":"IGFBP7 and CCT2 are novel lactylation-driven mediators of endothelial-to-mesenchymal transition in idiopathic pulmonary fibrosis.","date":"2025","source":"Functional & integrative genomics","url":"https://pubmed.ncbi.nlm.nih.gov/41261179","citation_count":0,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"41168408","id":"PMC_41168408","title":"CRISPR/Cas9 library screening uncovered CCT2 as a critical driver of acquired resistance to EGFR-targeted therapy by stabilizing TMX1 in non-small cell lung cancer.","date":"2025","source":"Cell death and differentiation","url":"https://pubmed.ncbi.nlm.nih.gov/41168408","citation_count":0,"is_preprint":false,"source_track":"pubmed_title"},{"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,"source_track":"pubmed_title"},{"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":0,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"42003909","id":"PMC_42003909","title":"CCT2 Orchestrates Glycolysis and Exosome-Mediated M2 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,"source_track":"pubmed_title"},{"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,"source_track":"pubmed_title"},{"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,"source_track":"pubmed_title"},{"pmid":"22658674","id":"PMC_22658674","title":"Insights into RNA biology from an atlas of mammalian mRNA-binding proteins.","date":"2012","source":"Cell","url":"https://pubmed.ncbi.nlm.nih.gov/22658674","citation_count":1718,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"12477932","id":"PMC_12477932","title":"Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences.","date":"2002","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/12477932","citation_count":1479,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"20562859","id":"PMC_20562859","title":"Network organization of the human autophagy system.","date":"2010","source":"Nature","url":"https://pubmed.ncbi.nlm.nih.gov/20562859","citation_count":1286,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"26186194","id":"PMC_26186194","title":"The BioPlex Network: A Systematic Exploration of the Human Interactome.","date":"2015","source":"Cell","url":"https://pubmed.ncbi.nlm.nih.gov/26186194","citation_count":1118,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"28514442","id":"PMC_28514442","title":"Architecture of the human interactome defines protein communities and disease networks.","date":"2017","source":"Nature","url":"https://pubmed.ncbi.nlm.nih.gov/28514442","citation_count":1085,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"26496610","id":"PMC_26496610","title":"A human interactome in three quantitative dimensions organized by stoichiometries and abundances.","date":"2015","source":"Cell","url":"https://pubmed.ncbi.nlm.nih.gov/26496610","citation_count":1015,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"25416956","id":"PMC_25416956","title":"A proteome-scale map of the human interactome network.","date":"2014","source":"Cell","url":"https://pubmed.ncbi.nlm.nih.gov/25416956","citation_count":977,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"15635413","id":"PMC_15635413","title":"Nucleolar proteome dynamics.","date":"2005","source":"Nature","url":"https://pubmed.ncbi.nlm.nih.gov/15635413","citation_count":934,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"32296183","id":"PMC_32296183","title":"A reference map of the human binary protein interactome.","date":"2020","source":"Nature","url":"https://pubmed.ncbi.nlm.nih.gov/32296183","citation_count":849,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"19490893","id":"PMC_19490893","title":"A genome-wide RNAi screen identifies multiple synthetic lethal interactions with the Ras oncogene.","date":"2009","source":"Cell","url":"https://pubmed.ncbi.nlm.nih.gov/19490893","citation_count":843,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"29507755","id":"PMC_29507755","title":"VIRMA mediates preferential m6A mRNA methylation in 3'UTR and near stop codon and associates with alternative polyadenylation.","date":"2018","source":"Cell discovery","url":"https://pubmed.ncbi.nlm.nih.gov/29507755","citation_count":829,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"33961781","id":"PMC_33961781","title":"Dual proteome-scale networks reveal cell-specific remodeling of the human interactome.","date":"2021","source":"Cell","url":"https://pubmed.ncbi.nlm.nih.gov/33961781","citation_count":705,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"22939629","id":"PMC_22939629","title":"A census of human soluble protein complexes.","date":"2012","source":"Cell","url":"https://pubmed.ncbi.nlm.nih.gov/22939629","citation_count":689,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"26912792","id":"PMC_26912792","title":"An improved smaller biotin ligase for BioID proximity labeling.","date":"2016","source":"Molecular biology of the cell","url":"https://pubmed.ncbi.nlm.nih.gov/26912792","citation_count":665,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"26472760","id":"PMC_26472760","title":"Gene essentiality and synthetic lethality in haploid human cells.","date":"2015","source":"Science (New York, N.Y.)","url":"https://pubmed.ncbi.nlm.nih.gov/26472760","citation_count":657,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"21873635","id":"PMC_21873635","title":"Phylogenetic-based propagation of functional annotations within the Gene Ontology consortium.","date":"2011","source":"Briefings in bioinformatics","url":"https://pubmed.ncbi.nlm.nih.gov/21873635","citation_count":656,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"18976975","id":"PMC_18976975","title":"Genome-scale RNAi screen for host factors required for HIV replication.","date":"2008","source":"Cell host & microbe","url":"https://pubmed.ncbi.nlm.nih.gov/18976975","citation_count":627,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"19056867","id":"PMC_19056867","title":"Large-scale proteomics and phosphoproteomics of urinary exosomes.","date":"2008","source":"Journal of the American Society of Nephrology : JASN","url":"https://pubmed.ncbi.nlm.nih.gov/19056867","citation_count":607,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"29395067","id":"PMC_29395067","title":"High-Density Proximity Mapping Reveals the Subcellular Organization of mRNA-Associated Granules and Bodies.","date":"2018","source":"Molecular cell","url":"https://pubmed.ncbi.nlm.nih.gov/29395067","citation_count":580,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"28302793","id":"PMC_28302793","title":"Anticancer sulfonamides target splicing by inducing RBM39 degradation via recruitment to DCAF15.","date":"2017","source":"Science (New York, N.Y.)","url":"https://pubmed.ncbi.nlm.nih.gov/28302793","citation_count":533,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"18391951","id":"PMC_18391951","title":"Many sequence variants affecting diversity of adult human height.","date":"2008","source":"Nature genetics","url":"https://pubmed.ncbi.nlm.nih.gov/18391951","citation_count":520,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"12665801","id":"PMC_12665801","title":"Exploring proteomes and analyzing protein processing by mass spectrometric identification of sorted N-terminal peptides.","date":"2003","source":"Nature biotechnology","url":"https://pubmed.ncbi.nlm.nih.gov/12665801","citation_count":485,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"15489334","id":"PMC_15489334","title":"The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC).","date":"2004","source":"Genome research","url":"https://pubmed.ncbi.nlm.nih.gov/15489334","citation_count":438,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"26638075","id":"PMC_26638075","title":"A Dynamic Protein Interaction Landscape of the Human Centrosome-Cilium Interface.","date":"2015","source":"Cell","url":"https://pubmed.ncbi.nlm.nih.gov/26638075","citation_count":433,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"35271311","id":"PMC_35271311","title":"OpenCell: Endogenous tagging for the cartography of human cellular organization.","date":"2022","source":"Science (New York, N.Y.)","url":"https://pubmed.ncbi.nlm.nih.gov/35271311","citation_count":432,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"23245942","id":"PMC_23245942","title":"Role of TAZ as mediator of Wnt signaling.","date":"2012","source":"Cell","url":"https://pubmed.ncbi.nlm.nih.gov/23245942","citation_count":407,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"26344197","id":"PMC_26344197","title":"Panorama of ancient metazoan macromolecular complexes.","date":"2015","source":"Nature","url":"https://pubmed.ncbi.nlm.nih.gov/26344197","citation_count":407,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"15324660","id":"PMC_15324660","title":"Proteomic, functional, and domain-based analysis of in vivo 14-3-3 binding proteins involved in cytoskeletal regulation and cellular organization.","date":"2004","source":"Current biology : CB","url":"https://pubmed.ncbi.nlm.nih.gov/15324660","citation_count":386,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"16009940","id":"PMC_16009940","title":"Human ISG15 conjugation targets both IFN-induced and constitutively expressed proteins functioning in diverse cellular pathways.","date":"2005","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/16009940","citation_count":383,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"26414014","id":"PMC_26414014","title":"Proteome-wide profiling of protein assemblies by cross-linking mass spectrometry.","date":"2015","source":"Nature methods","url":"https://pubmed.ncbi.nlm.nih.gov/26414014","citation_count":370,"is_preprint":false,"source_track":"gene2pubmed"}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":18160,"output_tokens":4625,"usd":0.061928},"stage2":{"model":"claude-opus-4-6","input_tokens":8147,"output_tokens":3253,"usd":0.18309},"total_usd":0.568467,"stage1_batch_id":"msgbatch_011kfMfE81o6CTcyhVUqumuW","stage2_batch_id":"msgbatch_01DTputS6WNkH745x1nVSoBo","note":"batch pricing = 50% of standard","round2_stage1":{"model":"claude-sonnet-4-6","input_tokens":29757,"output_tokens":5874,"usd":0.088691},"round2_rules_fired":"R3","round2_stage2":{"model":"claude-opus-4-6","input_tokens":9721,"output_tokens":4316,"usd":0.234758}},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2022,\n      \"finding\": \"CCT2 functions as an aggrephagy receptor that binds aggregation-prone proteins independently of cargo ubiquitination and interacts 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. CCT2 specifically promotes autophagic degradation of solid protein aggregates (low liquidity) but not liquid condensates, and acts independently of ubiquitin-binding receptors P62, NBR1, TAX1BP1, and chaperone-mediated autophagy.\",\n      \"method\": \"Co-immunoprecipitation, in vitro binding assays, mutagenesis of VLIR motif, live-cell imaging, loss-of-function in cell lines and mouse brain, biochemical fractionation\",\n      \"journal\": \"Cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — multiple orthogonal methods, replicated across cell and in vivo models, highly cited foundational paper\",\n      \"pmids\": [\"35366418\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"CCT2-Atg8 binding during solid aggrephagy is governed by two distinct regulatory mechanisms: (1) Atg1 kinase phosphorylates CCT2 at Ser412 and Ser470, and disruption of these sites impairs solid aggrephagy by hindering CCT2-Atg8 binding; (2) Atg11 (selective autophagy adaptor) directly associates with CCT2 through its CC4 domain, and deficiency of this interaction weakens CCT2-Atg8 association. Both regulatory mechanisms are conserved in mammalian cells (CCT2-LC3C binding).\",\n      \"method\": \"Phosphorylation site mutagenesis, in vitro kinase assay, co-immunoprecipitation, genetic epistasis (yeast and mammalian cells), domain mapping\",\n      \"journal\": \"EMBO reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — reconstitution of phosphorylation, mutagenesis, epistasis, conserved in two systems\",\n      \"pmids\": [\"39322741\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"The LCA-causing double mutation T400P/R516H in CCT2 (corresponding to T394P/R510H in yeast CCT2) reduces the ADP off-rate during ATP hydrolysis by CCT/TRiC, stabilizing the closed state of the complex and impeding exit of CCT2 monomers required for its autophagy function. ATPase activity of CCT/TRiC is also stimulated by a non-folded substrate.\",\n      \"method\": \"Steady-state and transient kinetic analysis, ATPase assay, yeast CCT2 double mutant biochemistry\",\n      \"journal\": \"Communications biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — in vitro biochemical reconstitution with kinetic analysis of mutant vs wild-type\",\n      \"pmids\": [\"37644231\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Compound heterozygous LCA-causative mutations in CCT2 (T400P and R516H) produce biochemically unstable CCTβ protein with reduced affinity for adjacent subunit CCTγ, leading to chaperonin complex instability. In mouse retina, CCTβ and CCTγ are expressed in retinal ganglion cells and connecting cilium of photoreceptors. CCT2 knockdown decreases its client protein Gβ1 (transducin β1), and wild-type but not mutant CCTβ rescues proliferation defects in 661W cells.\",\n      \"method\": \"Biochemical stability assays, co-immunoprecipitation, patient-derived iPSCs, siRNA knockdown rescue experiments, immunofluorescence in mouse retina\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — multiple orthogonal methods including patient mutations, iPSCs, and in vitro rescue\",\n      \"pmids\": [\"27645772\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Loss-of-function cct2 mutation (L394H-7del) in zebrafish causes small eye phenotype, attenuated retinal ganglion cell differentiation, disrupted retinal cell cycle, and increased neural retinal cell death. Injection of wild-type human CCTβ RNA rescues the small eye phenotype, reduces retinal cell death, and restores CCTβ and its client protein Gβ1. This establishes CCT2 as essential for retinal development by regulating the cell cycle.\",\n      \"method\": \"CRISPR-Cas9 knockout zebrafish, immunostaining, TUNEL assay, EdU assay, mRNA rescue experiment, western blot\",\n      \"journal\": \"Investigative ophthalmology & visual science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — clean KO with specific phenotype, mRNA rescue confirms specificity, orthogonal readouts\",\n      \"pmids\": [\"29450543\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"CCT2 directly binds to KRAS protein, leading to increased KRAS stability and upregulated downstream KRAS signaling. Dihydroartemisinin directly binds CCT2 and decreases KRAS expression and downstream signaling. CCT2 overexpression rescues the inhibitory effect of dihydroartemisinin on glioblastoma, confirming the CCT2-KRAS axis.\",\n      \"method\": \"Co-immunoprecipitation, mass spectrometry, surface plasmon resonance, overexpression rescue experiments, xenograft animal model\",\n      \"journal\": \"Cancer letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1–2 — SPR confirms direct binding, functional rescue confirms pathway placement, single lab\",\n      \"pmids\": [\"38582394\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"CCT2 recruits the HSP105-PP2A dephosphorylation complex to β-catenin via direct physical interaction, preventing phosphorylation-induced proteasomal degradation of β-catenin and resulting in intracellular accumulation of active β-catenin and increased Wnt signaling activity in ovarian cancer cells.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay, siRNA knockdown, overexpression, western blot\",\n      \"journal\": \"Molecular biology reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 — co-IP establishes complex, functional assays confirm signaling consequence, single lab\",\n      \"pmids\": [\"38165547\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"The E3 ubiquitin ligase TRIM21 directly facilitates CCT2 ubiquitination and degradation, reversing pro-tumor effects of CCT2. CCT2 promotes breast cancer growth and metastasis through activation of the JAK2/STAT3 signaling pathway.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay, siRNA knockdown, western blot, in vitro functional assays\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 — TRIM21 identified as E3 ligase for CCT2 with functional consequences, single lab\",\n      \"pmids\": [\"39079960\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Hypoxia enhances the interaction between Gli-1 (Hedgehog signaling factor) and CCT2, and CCT2 regulates Gli-1 folding. Reduction of CCT2 promotes ubiquitination-mediated Gli-1 degradation by β-TrCP due to incomplete Gli-1 folding. CCT2 knockdown inhibits Gli-1-driven tumor induction in colorectal cancer.\",\n      \"method\": \"Mass spectrometry, western blot, immunofluorescence, co-immunoprecipitation, siRNA knockdown, xenograft model\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 — MS identifies interaction, functional knockdown shows Gli-1 degradation consequence, single lab\",\n      \"pmids\": [\"31462707\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"PRRSV nsp3 enhances the interaction between porcine MDA5 and CCT2 (the aggrephagy receptor), promoting formation of MDA5-CCT2-nsp3 aggregates and their ubiquitination-independent autophagic clearance, leading to innate immune suppression.\",\n      \"method\": \"Co-immunoprecipitation, western blot, autophagy flux assays, siRNA knockdown in virus-infected cells\",\n      \"journal\": \"Virologica Sinica\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 — co-IP establishes ternary complex, functional data shows MDA5 clearance, single lab\",\n      \"pmids\": [\"38272236\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"LASV matrix protein (LASV-Z) interacts with CCT2 via glutamine at position 29 and tyrosine at position 48 of LASV-Z, hindering actin and tubulin folding by CCT2. Cytoskeleton disruption from this interaction hampers lysosomal enzyme transit and inhibits autophagosome-lysosome fusion, causing autophagosome accumulation that promotes viral budding. Mutation of LASV-Z interaction sites reduces CCT2 binding and restores autophagic flux.\",\n      \"method\": \"Co-immunoprecipitation, site-directed mutagenesis of LASV-Z, transmission electron microscopy, western blot, virus-like particle budding assay\",\n      \"journal\": \"Autophagy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — mutagenesis maps interaction interface, functional consequences demonstrated with orthogonal methods\",\n      \"pmids\": [\"39007910\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"CCT2 is identified as a regulator of cGAS-STING signaling; it associates with cGAS and attenuates cGAS-STING signaling by facilitating autophagy-mediated turnover of DNA-bound cGAS aggregates, limiting persistence of immunostimulatory cytosolic DNA signals.\",\n      \"method\": \"Site-specific photo-cross-linking coupled with quantitative proteomics, functional autophagy assays, co-immunoprecipitation\",\n      \"journal\": \"ACS chemical biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1–2 — novel photo-cross-linking proteomics method identifies interaction, functional validation of aggrephagy mechanism\",\n      \"pmids\": [\"42043443\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"CCT2 recruits TRIM28 to catalyze SUMO2 modification of TMX1, inhibiting its ubiquitination and enhancing TMX1 protein stability. TMX1-dependent ROS clearance confers resistance to third-generation EGFR-TKIs in NSCLC, establishing the CCT2/TRIM28/TMX1/ROS axis as a resistance mechanism.\",\n      \"method\": \"CRISPR/Cas9 genome-wide screen, TMT proteomics, co-immunoprecipitation, ubiquitination assay, SUMO modification assay, xenograft model\",\n      \"journal\": \"Cell death and differentiation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multi-omics discovery validated by co-IP and PTM assays, functional rescue in vivo, single lab\",\n      \"pmids\": [\"41168408\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"CCT2 knockdown in CCT5-co-depleted cells reduces levels of Cdc20 protein and reverses CDK4 degradation and apoptosis induced by MDRV p10.8 protein, indicating that CCT2 (and CCT5) are required for stabilization of Cdc20, which in turn mediates cell cycle arrest and apoptosis.\",\n      \"method\": \"siRNA depletion, western blot, cell cycle analysis, apoptosis assays\",\n      \"journal\": \"Veterinary microbiology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — genetic depletion shows phenotype but mechanism of CCT2-Cdc20 stabilization not directly demonstrated\",\n      \"pmids\": [\"31282373\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"CCT2 directly interacts with and stabilizes the glycolytic enzyme ALDOA, promoting glycolysis (increased extracellular acidification rate, glucose uptake, and lactate production) in HCC cells. CCT2 also promotes M2 macrophage polarization through exosome-mediated mechanisms.\",\n      \"method\": \"Co-immunoprecipitation, GST pulldown assay, extracellular acidification rate measurement, metabolomic profiling, THP1 co-culture assays\",\n      \"journal\": \"International journal of biological sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1–2 — GST pulldown confirms direct interaction, metabolic assays confirm functional consequence\",\n      \"pmids\": [\"42003909\"],\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, suppresses CD154 (CD40L) synthesis in CD4+ T cells, and modulates CD154 membranous expression via the Ca2+-calcineurin-NFAT1 signaling pathway.\",\n      \"method\": \"Protein mass spectrometry of EVs, western blot, flow cytometry, in vivo liver IRI mouse model, siRNA knockdown\",\n      \"journal\": \"Advanced science\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — MS identifies CCT2 in EVs, Ca2+ pathway inferred from signaling assays without direct mechanistic demonstration of CCT2-channel interaction\",\n      \"pmids\": [\"32999825\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"In the BBS/CCT chaperonin co-complex, CCT2 (along with CCT3 and BBS6) is required for localization of the adhesion GPCR ADGRV1 to primary cilia. Knockdown of CCT2 reduces ciliated cell numbers and shortens primary cilia. In the absence of TRiC/CCT-BBS components, ADGRV1 is depleted from the ciliary base and degraded via the proteasome.\",\n      \"method\": \"siRNA knockdown, immunofluorescence, ciliogenesis assays in cultured cells, co-immunoprecipitation\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — preprint, single lab, knockdown phenotype without direct mechanistic reconstitution of chaperone-client folding\",\n      \"pmids\": [\"bio_10.1101_2024.10.31.621306\"],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"In a compound heterozygous mouse model of LCA (CCT2 T400P/R516H), R516H homozygosity causes photoreceptor degeneration with significant depletion of TRiC/CCT substrate proteins in retina. T400P homozygosity causes embryonic lethality. CCDC181 is identified as an interacting protein for CCTβ, and its localization to photoreceptor connecting cilia is compromised in the compound heterozygous mutant mouse.\",\n      \"method\": \"Knock-in mouse model generation, retinal histology, western blot for TRiC substrates, co-immunoprecipitation (CCDC181), immunofluorescence\",\n      \"journal\": \"Communications biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — in vivo mammalian model with defined phenotypic readout and identification of novel interacting client protein\",\n      \"pmids\": [\"38830954\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"CCT2 is a dual-function protein that acts as a chaperonin subunit within the TRiC/CCT complex to fold client proteins (including Gβ1, KRAS, ALDOA, tubulin, and actin), and switches to a monomeric aggrephagy receptor that binds solid protein aggregates via a VLIR motif and interacts with ATG8/LC3 proteins independently of ubiquitin; this switch is triggered by aggregate-induced CCT2 monomer formation and is regulated by Atg1-mediated phosphorylation of CCT2 at Ser412/Ser470 and by Atg11 adaptor binding, while the LCA-causing T400P/R516H double mutation stabilizes the closed TRiC complex by reducing ADP off-rate, thereby preventing CCT2 monomer release and impairing aggrephagy.\"\n}\n```\n\n--- ROUND 2 (R2/R3, augmented corpus) ---\n\n```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2022,\n      \"finding\": \"CCT2 functions as an aggrephagy receptor that binds aggregation-prone proteins independent of cargo ubiquitination and interacts with autophagosome marker ATG8s through a non-classical VLIR motif. Unlike ubiquitin-binding receptors (P62, NBR1, TAX1BP1), CCT2 specifically promotes autophagic degradation of solid protein aggregates with little liquidity. Accumulation of aggregation-prone proteins induces a functional switch of CCT2 from a chaperone subunit to an autophagy receptor by promoting CCT2 monomer formation, which exposes the VLIR motif for ATG8 interaction.\",\n      \"method\": \"Co-IP, pulldown, live-cell imaging, loss-of-function experiments in cells and mouse brain, domain mutagenesis (VLIR motif), fractionation assays distinguishing solid vs. liquid aggregates\",\n      \"journal\": \"Cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — multiple orthogonal methods, mechanistic rescue experiments, in vivo mouse brain model, replicated in commentary (PMID:35699934)\",\n      \"pmids\": [\"35366418\"],\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 and suppress CD154 (CD40L) synthesis in CD4+ T cells via the Ca2+-calcineurin-NFAT1 signaling pathway, thereby modulating inflammatory responses during liver ischemia/reperfusion injury.\",\n      \"method\": \"Protein mass spectrometry identification of CCT2 in EVs, in vivo liver IRI mouse model, mechanistic pathway analysis of Ca2+-calcineurin-NFAT1 signaling, flow cytometry for CD154 expression\",\n      \"journal\": \"Advanced science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 — identified by MS, functional in vivo validation, mechanistic pathway placed but Ca2+ channel identity not fully resolved\",\n      \"pmids\": [\"32999825\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"CCT2 (along with TCP1) is essential for survival of breast cancer cells; both genes encode subunits of the TRiC chaperonin complex and are recurrently amplified and overexpressed in breast cancer, with TCP1 expression regulated by PI3K signaling downstream of driver oncogene activation.\",\n      \"method\": \"RNAi-based functional genetic screen, copy number analysis, expression profiling, siRNA knockdown viability assays, PI3K pathway inhibition\",\n      \"journal\": \"Experimental cell research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — RNAi functional screen with epistasis to PI3K signaling, but mechanistic detail on CCT2 specifically is limited\",\n      \"pmids\": [\"25704758\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"CCT2 (T-complex protein 1 subunit beta) interacts with Gli-1 under hypoxic conditions in colorectal cancer cells, facilitating Gli-1 folding and preventing its ubiquitination-mediated degradation by β-TrCP; reduction of CCT2 inhibits Gli-1-driven tumor induction.\",\n      \"method\": \"Mass spectrometry identification of CCT2-Gli-1 interaction, western blotting, immunofluorescence, RNAi knockdown, in vivo xenograft models\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 — MS-identified interaction with functional validation in vivo, but direct folding assay not performed\",\n      \"pmids\": [\"31462707\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Compound heterozygous mutations T400P and R516H in CCT2 (CCTβ) cause Leber congenital amaurosis (LCA) by destabilizing the chaperonin complex; mutant CCTβ proteins show reduced affinity for adjacent subunit CCTγ, impair proliferation in patient-derived iPSCs, fail to rescue knockdown phenotypes, and reduce the major client protein transducin β1 (Gβ1) in mouse retina where CCTβ and CCTγ are co-expressed in retinal ganglion cells and photoreceptor connecting cilia.\",\n      \"method\": \"Biochemical stability assays of mutant proteins, co-IP for CCTβ-CCTγ interaction, patient-derived iPSC proliferation assays, rescue experiments in 661W cells, Cct2 knockdown, immunostaining of mouse retina\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — multiple orthogonal methods including biochemical interaction assays, cellular rescue, and in vivo retinal characterization\",\n      \"pmids\": [\"27645772\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Loss-of-function cct2 mutation (L394H-7del) in zebrafish causes small eye phenotype, attenuated retinal ganglion cell differentiation, disrupted retinal cell cycle, and increased neural retinal cell death; injection of wild-type human CCTβ RNA rescues the phenotype and restores Gβ1 protein levels, confirming CCT2's essential role in retinal development through cell cycle regulation.\",\n      \"method\": \"CRISPR-Cas9 mutagenesis, microscopy, immunostaining, TUNEL assay, EdU proliferation assay, RNA rescue injection\",\n      \"journal\": \"Investigative ophthalmology & visual science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — CRISPR loss-of-function with genetic rescue, multiple cellular readouts, ortholog of human CCT2\",\n      \"pmids\": [\"29450543\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"CCT2 and CCT5 are required for stabilization of Cdc20, which is necessary for MDRV p10.8-induced CDK4 degradation via the ubiquitin-proteasome pathway and subsequent cell cycle arrest and apoptosis; depletion of CCT2 reduced Cdc20 levels and reversed p10.8-mediated CDK4 degradation and apoptosis.\",\n      \"method\": \"siRNA depletion of CCT2/CCT5 and Cdc20, western blotting for CDK4/Cdc20 levels, apoptosis assays, cell cycle analysis\",\n      \"journal\": \"Veterinary microbiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 — functional RNAi epistasis linking CCT2 to Cdc20 stability and downstream cell cycle control, but only in viral infection context\",\n      \"pmids\": [\"31282373\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"The LCA-causative double mutation T400P/R516H in yeast CCT2 reduces the off-rate of ADP during ATP hydrolysis by CCT/TRiC, stabilizing the closed state of the chaperonin complex; this impedes CCT2 monomer exit from the complex required for its autophagy receptor function. ATPase activity of CCT/TRiC is stimulated by a non-folded substrate.\",\n      \"method\": \"Steady-state and transient kinetic analysis of ATPase activity in yeast CCT/TRiC carrying equivalent mutations, substrate-stimulated ATPase assays\",\n      \"journal\": \"Communications biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — rigorous in vitro biochemical kinetic analysis with mutant variants directly explaining the LCA mechanistic defect in autophagy function\",\n      \"pmids\": [\"37644231\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"CCT2-mediated aggrephagy is regulated by two mechanisms in yeast (conserved in mammals): (1) Atg1 kinase phosphorylates Cct2 at Ser412 and Ser470, and disruption of these sites impairs solid aggrephagy by hindering Cct2-Atg8 binding; (2) Atg11 (selective autophagy adaptor) directly associates with Cct2 through its CC4 domain, and loss of this interaction weakens Cct2-Atg8 association.\",\n      \"method\": \"Phosphorylation site mutagenesis, in vivo phosphorylation assays, co-IP, domain mapping of Atg11-Cct2 interaction, aggrephagy functional assays, conservation validated in mammalian cells with LC3C\",\n      \"journal\": \"EMBO reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — mutagenesis of phosphorylation sites, domain-resolved interaction mapping, functional aggrephagy readouts, conserved in mammalian cells\",\n      \"pmids\": [\"39322741\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"E3 ubiquitin ligase Trim21 facilitates CCT2 ubiquitination and proteasomal degradation in breast cancer cells, reversing CCT2's pro-tumorigenic effects. CCT2 promotes cancer progression via JAK2/STAT3 signaling activation. Exosomal CCT2 from breast cancer cells suppresses CD4+ T cell activation by constraining Ca2+-NFAT1 signaling and reducing CD40L (CD154) expression.\",\n      \"method\": \"Co-IP for Trim21-CCT2 interaction, ubiquitination assay, CCT2 knockdown/overexpression with JAK2/STAT3 pathway readouts, exosome isolation and treatment experiments, Ca2+-NFAT1 signaling analysis\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 — co-IP-confirmed ubiquitination, pathway activation shown by KD/OE with multiple readouts, mechanistic detail on Ca2+ channel not fully resolved\",\n      \"pmids\": [\"39079960\"],\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 the MDA5-CCT2-nsp3 complex independently of ubiquitination, thereby suppressing innate immune signaling via CCT2's aggrephagy receptor function.\",\n      \"method\": \"Co-IP for MDA5-CCT2-nsp3 interaction, autophagy flux assays, MDA5 aggregate formation analysis, nsp3 overexpression, PRRSV infection model\",\n      \"journal\": \"Virologica Sinica\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 — co-IP with functional autophagic clearance assay, but in viral infection context with multiple simultaneous variables\",\n      \"pmids\": [\"38272236\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"CCT2 directly binds to KRAS protein (shown by co-IP, mass spectrometry, and surface plasmon resonance), leading to increased KRAS stability and upregulated downstream KRAS signaling in glioblastoma. Dihydroartemisinin directly binds CCT2 and decreases KRAS expression and signaling; CCT2 overexpression rescues the inhibitory effect of dihydroartemisinin.\",\n      \"method\": \"Co-immunoprecipitation, mass spectrometry, surface plasmon resonance (direct binding measurement), CCT2 overexpression rescue, glioblastoma animal model\",\n      \"journal\": \"Cancer letters\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — three orthogonal binding methods (Co-IP, MS, SPR) with functional rescue and in vivo validation\",\n      \"pmids\": [\"38582394\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"LASV matrix protein (LASV-Z) interacts with CCT2 via glutamine-29 and tyrosine-48 residues, hindering actin and tubulin folding; cytoskeleton disruption caused by this interaction blocks lysosomal enzyme transit and autophagosome-lysosome fusion, promoting autophagosome accumulation that facilitates LASV-like particle budding. Mutation of the LASV-Z interaction sites reduces CCT2 binding and restores autophagic flux.\",\n      \"method\": \"Co-IP, site-directed mutagenesis of LASV-Z interaction residues, autophagy flux assays (LC3/LAMP1 co-localization), cytoskeleton disruption analysis, VLP budding assay\",\n      \"journal\": \"Autophagy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — co-IP with mutagenesis validation and functional autophagic flux readout, links CCT2 cytoskeletal folding function to viral life cycle\",\n      \"pmids\": [\"39007910\"],\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 with increased Wnt signaling.\",\n      \"method\": \"Co-IP for CCT2-β-catenin and CCT2-HSP105-PP2A interactions, ubiquitination assay, CCT2 KD/OE with Wnt pathway readouts, cancer stem cell functional assays\",\n      \"journal\": \"Molecular biology reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 — co-IP-confirmed three-way complex, dephosphorylation mechanism proposed with functional pathway readouts\",\n      \"pmids\": [\"38165547\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"CCT2 is identified as a critical mediator of acquired resistance to third-generation EGFR-TKIs in lung cancer; mechanistically, CCT2 recruits TRIM28 to catalyze SUMO2 modification of TMX1, inhibiting its ubiquitination and enhancing TMX1 protein stability, which promotes TMX1-dependent ROS clearance conferring drug resistance.\",\n      \"method\": \"CRISPR/Cas9 genome-wide screen, TMT proteomics, co-IP for CCT2-TRIM28-TMX1 complex, SUMO2 modification assay, ubiquitination assay, ROS measurement, xenograft models\",\n      \"journal\": \"Cell death and differentiation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — genome-wide CRISPR screen with proteomic validation and co-IP-confirmed PTM mechanism, in vivo xenograft validation\",\n      \"pmids\": [\"41168408\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"CCT2 knockdown reduces STAT3 phosphorylation and impairs HCC cell proliferation, migration, invasion, and stemness in vitro and in vivo; IL-6 treatment rescues phosphorylated STAT3 levels and counteracts CCT2 knockdown effects, placing CCT2 upstream of STAT3 activation in hepatocellular carcinoma.\",\n      \"method\": \"siRNA knockdown, EdU/colony formation/Transwell assays, flow cytometry, xenograft and hematogenous metastasis models, western blotting for p-STAT3, IL-6 rescue experiment\",\n      \"journal\": \"Oncology reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 — clean KD with defined phenotypic readout, epistasis established by IL-6 rescue, but direct CCT2-STAT3 interaction not shown\",\n      \"pmids\": [\"41789667\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Compound heterozygous Cct2 mutations (T400P/R516H) in mice cause aberrant cone cell lamination and early lethality; R516H homozygosity causes photoreceptor degeneration with significant depletion of TRiC/CCT substrate proteins in retina. CCDC181 is identified as a CCTβ-interacting protein whose localization to photoreceptor connecting cilia is compromised in mutant mice.\",\n      \"method\": \"Generation of knock-in mouse models, histology, immunostaining, retinal phenotyping, co-IP for CCTβ-CCDC181 interaction, localization analysis of ciliary proteins\",\n      \"journal\": \"Communications biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — mammalian genetic model with phenotypic characterization, new substrate/interactor (CCDC181) identified by co-IP with in vivo localization validation\",\n      \"pmids\": [\"38830954\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"CCT2 directly interacts with and stabilizes the glycolytic enzyme ALDOA, as shown by co-immunoprecipitation and GST pulldown, increasing extracellular acidification rate, glucose uptake, and lactate production in HCC cells. CCT2 also promotes M2 macrophage polarization through exosome-mediated mechanisms, creating an immunosuppressive tumor microenvironment; CCT2 knockdown enhances anti-tumor efficacy of PD-1 blockade in mouse models.\",\n      \"method\": \"Co-immunoprecipitation, GST pulldown assay, extracellular acidification rate measurement, glucose uptake assay, lactate quantification, metabolomics, THP1 co-culture assay, exosome treatment, in vivo xenograft with PD-1 blockade\",\n      \"journal\": \"International journal of biological sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1–2 — direct interaction confirmed by two binding assays (Co-IP + GST pulldown) with metabolic functional validation and in vivo immune modulation data\",\n      \"pmids\": [\"42003909\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"Site-specific photo-cross-linking coupled with quantitative proteomics identified CCT2 as a cGAS-associated factor; CCT2 attenuates cGAS-STING innate immune signaling by facilitating autophagy-mediated turnover of DNA-bound cGAS aggregates, limiting persistence of immunostimulatory cytosolic DNA signals.\",\n      \"method\": \"Residue-resolved photo-cross-linking, quantitative proteomics, cGAS-STING signaling assays, autophagy flux analysis, CCT2 loss-of-function\",\n      \"journal\": \"ACS chemical biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1–2 — novel photo-cross-linking proteomics method identifies interaction, functional signaling assays validate role, consistent with established CCT2 aggrephagy function\",\n      \"pmids\": [\"42043443\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Histone H3K18 lactylation upregulates METTL3 expression, which enhances CCT2 translation through m6A modification of CCT2 mRNA; elevated CCT2 in turn weakens CD8+ T cell activity by inhibiting Ca2+ influx, thereby mediating immune evasion in gastric cancer.\",\n      \"method\": \"CHIP for H3K18la at METTL3 locus, RIP assay for METTL3-CCT2 mRNA m6A modification, CCT2 overexpression/knockdown, Ca2+ influx measurement, T cell cytotoxicity assay, flow cytometry, homograft mouse model\",\n      \"journal\": \"Cellular and molecular life sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — RIP assay confirms m6A modification of CCT2 mRNA, functional Ca2+ and T cell readouts, rescue experiments, but CCT2-Ca2+ channel interaction not directly shown\",\n      \"pmids\": [\"41288742\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"CCT2 knockdown in primary cilia studies revealed that the TRiC/CCT chaperonin complex (including CCT2 and CCT3) forms a co-complex with BBS chaperonin-like proteins required for the localization of adhesion GPCR ADGRV1 to primary cilia; in the absence of this co-complex, ADGRV1 is depleted from the base of primary cilia and degraded via the proteasome.\",\n      \"method\": \"siRNA knockdown of CCT2/CCT3/BBS6, ciliogenesis phenotyping (ciliated cell count, cilia length), immunofluorescence localization of ADGRV1, proteasome inhibitor rescue\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — preprint, single-method knockdown with localization readout, no direct CCT2-ADGRV1 interaction demonstrated\",\n      \"pmids\": [\"bio_10.1101_2024.10.31.621306\"],\n      \"is_preprint\": true\n    }\n  ],\n  \"current_model\": \"CCT2 is a dual-function protein that acts canonically as a subunit of the TRiC/CCT chaperonin complex (folding substrates including tubulin, actin, Gβ1, KRAS, Gli-1, and ALDOA in an ATP-dependent manner) and, upon accumulation of solid protein aggregates, undergoes monomer formation that exposes a VLIR motif enabling it to switch function to serve as a ubiquitin-independent aggrephagy receptor that binds aggregation-prone solid aggregates and interacts with ATG8/LC3 proteins — a process regulated by Atg1-mediated phosphorylation at Ser412/Ser470 and direct Atg11 binding — while also modulating immune responses through Ca2+-NFAT signaling suppression in T cells and participating in cancer progression via stabilization of oncoproteins (KRAS, β-catenin) and activation of JAK2/STAT3 and Wnt pathways.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"CCT2 encodes the β subunit of the TRiC/CCT chaperonin complex and functions both as a chaperonin subunit that folds obligate clients—including Gβ1, KRAS, ALDOA, Gli-1, tubulin, and actin—and as an autonomous aggrephagy receptor that selectively targets solid protein aggregates for autophagic degradation independently of ubiquitin [PMID:35366418, PMID:27645772, PMID:38582394]. Accumulation of aggregation-prone substrates induces CCT2 monomer release from the TRiC complex, exposing a VLIR motif that binds ATG8/LC3 family proteins; this aggrephagy function is positively regulated by Atg1-mediated phosphorylation at Ser412/Ser470 and by the Atg11 adaptor [PMID:35366418, PMID:39322741]. Compound heterozygous CCT2 mutations (T400P/R516H) cause Leber congenital amaurosis by destabilizing the chaperonin complex, depleting retinal TRiC substrates, and reducing the ADP off-rate that normally permits CCT2 monomer exit for aggrephagy [PMID:27645772, PMID:37644231, PMID:38830954]. CCT2's aggrephagy receptor activity is exploited by viral proteins—PRRSV nsp3 hijacks it to degrade MDA5 for immune evasion, while LASV matrix protein sequesters it to block actin/tubulin folding and autophagosome–lysosome fusion [PMID:38272236, PMID:39007910].\",\n  \"teleology\": [\n    {\n      \"year\": 2016,\n      \"claim\": \"Establishing that CCT2 mutations cause human disease: compound heterozygous T400P/R516H mutations were shown to destabilize the CCTβ subunit, reduce its affinity for CCTγ, impair complex integrity, and diminish the client Gβ1, causally linking CCT2 to Leber congenital amaurosis.\",\n      \"evidence\": \"Biochemical stability assays, co-IP, patient iPSCs, siRNA rescue in 661W cells, immunofluorescence in mouse retina\",\n      \"pmids\": [\"27645772\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No structural explanation for how T400P/R516H destabilizes the complex\", \"Other retinal client proteins beyond Gβ1 not surveyed\", \"Heterozygote carrier phenotype not characterized\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"An in vivo requirement for CCT2 in retinal development was demonstrated: zebrafish cct2 knockout caused small eyes, retinal cell death, and cell cycle disruption, all rescued by human CCT2 mRNA injection, confirming the protein's essential role in vertebrate retinogenesis beyond the mouse LCA model.\",\n      \"evidence\": \"CRISPR-Cas9 zebrafish knockout, TUNEL and EdU assays, mRNA rescue, western blot for Gβ1\",\n      \"pmids\": [\"29450543\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism linking chaperonin loss to cell cycle disruption not defined\", \"Contribution of aggrephagy vs. folding function not distinguished\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"CCT2 was shown to fold Gli-1 under hypoxia: reduced CCT2 led to incomplete Gli-1 folding, β-TrCP–mediated ubiquitination, and degradation, establishing CCT2 as a regulator of Hedgehog signaling output in colorectal cancer.\",\n      \"evidence\": \"Mass spectrometry, co-IP, siRNA knockdown, xenograft model\",\n      \"pmids\": [\"31462707\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct chaperone–substrate folding intermediate not captured\", \"Whether CCT2 acts as monomer or within TRiC for Gli-1 folding unclear\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"A paradigm-shifting discovery revealed that CCT2 moonlights as an aggrephagy receptor: aggregate accumulation triggers CCT2 monomer release from TRiC, exposing a VLIR motif that binds ATG8 proteins to selectively deliver solid (not liquid) aggregates to autophagosomes, independent of ubiquitin-binding receptors.\",\n      \"evidence\": \"Co-IP, in vitro binding, VLIR mutagenesis, live-cell imaging, loss-of-function in cell lines and mouse brain, biochemical fractionation\",\n      \"pmids\": [\"35366418\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How aggregate sensing triggers monomer release mechanistically unknown\", \"Structural basis of VLIR–ATG8 interaction not resolved\", \"Whether other CCT subunits also exit as monomers not tested\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"The mechanistic basis of the LCA mutations was resolved at the enzymatic level: T400P/R516H reduces ADP off-rate from TRiC, trapping the complex in its closed state and preventing CCT2 monomer release required for aggrephagy, thus linking chaperonin ATPase kinetics to the dual-function switch.\",\n      \"evidence\": \"Steady-state and transient kinetic ATPase analysis of wild-type vs. mutant yeast CCT2\",\n      \"pmids\": [\"37644231\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"ADP off-rate effect not yet shown for human TRiC\", \"Relative contribution of impaired folding vs. impaired aggrephagy to LCA pathology not separated\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Regulatory control of the aggrephagy switch was defined: Atg1 kinase phosphorylates CCT2 at Ser412/Ser470 to promote ATG8 binding, and the Atg11 adaptor directly engages CCT2 via its CC4 domain, with both mechanisms conserved in mammalian CCT2–LC3C binding.\",\n      \"evidence\": \"In vitro kinase assay, phosphosite mutagenesis, co-IP, genetic epistasis in yeast and mammalian cells, domain mapping\",\n      \"pmids\": [\"39322741\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Phosphorylation stoichiometry in vivo not measured\", \"Whether Atg1 phosphorylation also affects TRiC complex stability not tested\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"CCT2's chaperonin and aggrephagy functions were shown to be exploited by viruses: PRRSV nsp3 redirects CCT2 aggrephagy to degrade MDA5 for immune evasion, while LASV matrix protein sequesters CCT2 to block actin/tubulin folding and autophagosome–lysosome fusion, promoting viral budding.\",\n      \"evidence\": \"Co-IP, mutagenesis of LASV-Z interaction residues, TEM, autophagy flux assays, virus-like particle budding\",\n      \"pmids\": [\"38272236\", \"39007910\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether viral hijacking targets monomeric or complex-bound CCT2 not resolved\", \"In vivo viral pathogenesis consequences not shown for LASV-Z mutants\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"CCT2 was identified as a direct interactor and stabilizer of KRAS, broadening its client repertoire to oncogenic signaling proteins and establishing a CCT2–KRAS axis in glioblastoma.\",\n      \"evidence\": \"Co-IP, mass spectrometry, SPR for direct binding, overexpression rescue, xenograft model\",\n      \"pmids\": [\"38582394\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether KRAS is folded by TRiC holoenzyme or monomeric CCT2 not distinguished\", \"Generalizability to other RAS isoforms not tested\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"An in vivo LCA mouse model confirmed that R516H homozygosity causes photoreceptor degeneration with global TRiC substrate depletion, and identified CCDC181 as a novel CCT2-interacting protein whose ciliary localization depends on CCT2 function.\",\n      \"evidence\": \"Knock-in mouse model, retinal histology, western blot for TRiC substrates, co-IP for CCDC181, immunofluorescence\",\n      \"pmids\": [\"38830954\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether CCDC181 is a direct folding client or indirect interactor not resolved\", \"Aggrephagy function not assessed in this mouse model\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"CCT2 was shown to directly bind and stabilize the glycolytic enzyme ALDOA, promoting glycolysis in hepatocellular carcinoma cells, expanding the metabolic client repertoire.\",\n      \"evidence\": \"GST pulldown, co-IP, extracellular acidification rate, metabolomic profiling\",\n      \"pmids\": [\"42003909\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether stabilization involves folding or protection from degradation not distinguished\", \"In vivo metabolic phenotype not assessed\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"A non-canonical scaffolding role for CCT2 was identified: it recruits the TRIM28 SUMO ligase to TMX1, promoting SUMO2 modification that protects TMX1 from ubiquitin-mediated degradation, establishing a CCT2/TRIM28/TMX1/ROS axis driving EGFR-TKI resistance in NSCLC.\",\n      \"evidence\": \"Genome-wide CRISPR screen, TMT proteomics, co-IP, SUMO and ubiquitination assays, xenograft model\",\n      \"pmids\": [\"41168408\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether CCT2 acts here as monomer or within TRiC not determined\", \"Direct structural basis for TRIM28 recruitment unknown\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Key unresolved questions include: how aggregate sensing triggers the structural transition from TRiC-incorporated CCT2 to autophagy-competent monomer; the structural basis of the VLIR–ATG8 interaction; and whether the chaperonin-folding and aggrephagy-receptor activities of CCT2 are quantitatively balanced or regulated by distinct upstream signals in different tissues.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No structural model of the monomer–TRiC equilibrium under aggregate stress\", \"Tissue-specific regulation of the dual function not characterized\", \"Relative pathogenic contribution of impaired folding vs. impaired aggrephagy in LCA not separated\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0044183\", \"supporting_discovery_ids\": [0, 3, 4, 5, 8, 14]},\n      {\"term_id\": \"GO:0038024\", \"supporting_discovery_ids\": [0, 1, 11]},\n      {\"term_id\": \"GO:0140657\", \"supporting_discovery_ids\": [2]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [6, 12]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [0, 3]},\n      {\"term_id\": \"GO:0005929\", \"supporting_discovery_ids\": [3, 17]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-9612973\", \"supporting_discovery_ids\": [0, 1, 10, 11]},\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [2, 3, 5, 8, 14]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [3, 4, 17]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [5, 6, 8]}\n    ],\n    \"complexes\": [\n      \"TRiC/CCT\"\n    ],\n    \"partners\": [\n      \"ATG8\",\n      \"LC3C\",\n      \"CCT5\",\n      \"KRAS\",\n      \"ALDOA\",\n      \"TRIM28\",\n      \"CCDC181\",\n      \"GLI1\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```\n\n--- ROUND 2 (R2/R3, augmented corpus) ---\n\n```json\n{\n  \"mechanistic_narrative\": \"CCT2 is a subunit of the TRiC/CCT chaperonin complex that folds obligate substrates including tubulin, actin, G-transducin β1, KRAS, Gli-1, and ALDOA in an ATP-dependent manner, and it moonlights as a ubiquitin-independent aggrephagy receptor for solid protein aggregates. When solid aggregates accumulate, CCT2 exits the TRiC complex as a monomer, exposing a non-classical VLIR motif that binds ATG8/LC3 family proteins; this receptor switch is positively regulated by Atg1-mediated phosphorylation at Ser412/Ser470 and by direct Atg11 binding, while LCA-causative mutations (T400P/R516H) impair ADP release and trap CCT2 in the closed complex, blocking both chaperone and aggrephagy functions [PMID:35366418, PMID:39322741, PMID:37644231]. Compound heterozygous CCT2 mutations cause Leber congenital amaurosis through destabilization of the TRiC complex and depletion of retinal client proteins including Gβ1 and CCDC181 at photoreceptor connecting cilia [PMID:27645772, PMID:38830954]. Beyond proteostasis, CCT2 promotes tumor progression by stabilizing oncoproteins such as KRAS and β-catenin, activating JAK2/STAT3 signaling, and suppressing anti-tumor immunity through inhibition of Ca²⁺-NFAT signaling in T cells [PMID:38582394, PMID:38165547, PMID:39079960, PMID:41288742].\",\n  \"teleology\": [\n    {\n      \"year\": 2015,\n      \"claim\": \"Establishing that CCT2, as a TRiC subunit, is essential for cancer cell survival answered whether individual chaperonin subunits are rate-limiting in proliferating cells and linked CCT2 to oncogenic dependency.\",\n      \"evidence\": \"RNAi functional genetic screen and copy number analysis in breast cancer cell lines\",\n      \"pmids\": [\"25704758\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Specific substrates mediating cancer cell essentiality were not identified\",\n        \"Whether CCT2 essentiality extends beyond breast cancer was untested\"\n      ]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Discovery that compound heterozygous CCT2 mutations (T400P/R516H) cause Leber congenital amaurosis revealed that TRiC integrity is critical for retinal cell survival and that Gβ1 is a key retinal client protein whose depletion underlies disease pathogenesis.\",\n      \"evidence\": \"Biochemical stability assays, co-IP for CCTβ–CCTγ interaction, patient iPSC proliferation assays, rescue in 661W cells, immunostaining of mouse retina\",\n      \"pmids\": [\"27645772\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Photoreceptor-specific versus retinal ganglion cell contributions to disease were unresolved\",\n        \"Whether partial TRiC disruption affects substrates beyond Gβ1 in retina was unknown\"\n      ]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Genetic validation in zebrafish demonstrated that CCT2 loss of function causes retinal degeneration and impaired cell cycle progression, and human CCTβ RNA rescue confirmed functional conservation across vertebrates.\",\n      \"evidence\": \"CRISPR-Cas9 cct2 mutagenesis in zebrafish with RNA rescue, TUNEL and EdU assays\",\n      \"pmids\": [\"29450543\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Which specific cell cycle regulators require CCT2 folding in retinal progenitors was not determined\",\n        \"Mechanism linking CCT2 to cell cycle regulation versus apoptosis not disentangled\"\n      ]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Identification of Gli-1 as a CCT2 client under hypoxia expanded the repertoire of cancer-relevant substrates, showing CCT2 prevents β-TrCP-mediated ubiquitination and degradation of an oncogenic transcription factor.\",\n      \"evidence\": \"Mass spectrometry identification of CCT2–Gli-1 interaction, RNAi knockdown, xenograft colorectal cancer model\",\n      \"pmids\": [\"31462707\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Direct in vitro folding assay for Gli-1 by CCT2 was not performed\",\n        \"Whether the interaction requires the intact TRiC complex or CCT2 monomers was unresolved\"\n      ]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Demonstration that CCT2 stabilizes Cdc20 revealed a link between the TRiC chaperonin and cell cycle checkpoint control, as CCT2 depletion reduced Cdc20 levels and reversed virus-induced CDK4 degradation.\",\n      \"evidence\": \"siRNA depletion of CCT2/CCT5 with Cdc20 and CDK4 western blotting, apoptosis and cell cycle assays in MDRV-infected cells\",\n      \"pmids\": [\"31282373\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Only tested in viral infection context; unclear if Cdc20 is a TRiC client in uninfected cells\",\n        \"Direct CCT2–Cdc20 physical interaction not shown\"\n      ]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Finding that extracellular vesicle–delivered CCT2 suppresses CD4⁺ T cell activation through Ca²⁺-calcineurin-NFAT1 signaling established a non-chaperone immunomodulatory role for CCT2 in the extracellular compartment.\",\n      \"evidence\": \"Mass spectrometry of UC-MSC-derived EVs, liver IRI mouse model, flow cytometry for CD154, Ca²⁺-calcineurin-NFAT1 pathway analysis\",\n      \"pmids\": [\"32999825\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Identity of the calcium channel regulated by CCT2 was not resolved\",\n        \"Whether CCT2 acts as monomer or oligomer in EVs was not determined\"\n      ]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"The landmark discovery that CCT2 functions as a ubiquitin-independent aggrephagy receptor fundamentally redefined CCT2 as a bifunctional protein: aggregate accumulation triggers CCT2 monomer release from TRiC, exposing a VLIR motif for ATG8 binding and selective clearance of solid (not liquid) aggregates.\",\n      \"evidence\": \"Co-IP, pulldown, live-cell imaging, VLIR motif mutagenesis, fractionation of solid vs. liquid aggregates, loss-of-function in cells and mouse brain\",\n      \"pmids\": [\"35366418\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"The structural basis for the monomer–oligomer switch was not resolved\",\n        \"Whether CCT2 aggrephagy is active in all cell types was not established\",\n        \"Signals triggering monomerization beyond aggregate accumulation were unknown\"\n      ]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Kinetic analysis of LCA-causative CCT2 mutations revealed that T400P/R516H slows ADP off-rate, stabilizing the closed TRiC state and trapping CCT2 within the complex, thereby explaining how these mutations simultaneously impair both chaperonin cycling and aggrephagy receptor availability.\",\n      \"evidence\": \"Steady-state and transient kinetic ATPase assays on yeast TRiC carrying equivalent mutations, substrate-stimulated ATPase measurements\",\n      \"pmids\": [\"37644231\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Whether the kinetic defect affects all TRiC substrates equally or selectively was untested\",\n        \"Structural detail of how mutations alter the ADP binding pocket was not determined\"\n      ]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Elucidation of the regulatory mechanisms controlling CCT2 aggrephagy showed that Atg1-mediated phosphorylation (Ser412/Ser470) and direct Atg11 binding both promote CCT2–ATG8 interaction, providing the first upstream signaling pathway governing the chaperone-to-receptor switch.\",\n      \"evidence\": \"Phosphorylation site mutagenesis, in vivo phosphorylation assays, domain mapping of Atg11–Cct2 interaction, aggrephagy assays in yeast and mammalian cells\",\n      \"pmids\": [\"39322741\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Mammalian kinase equivalent of Atg1 acting on CCT2 confirmed only for conservation, not fully characterized\",\n        \"Whether other post-translational modifications regulate the switch was unknown\"\n      ]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Multiple studies converged to show CCT2 stabilizes diverse oncoproteins—KRAS via direct binding (confirmed by SPR), β-catenin via recruitment of the HSP105–PP2A dephosphorylation complex—and activates JAK2/STAT3 signaling, establishing CCT2 as a multi-pathway oncogenic chaperone.\",\n      \"evidence\": \"Co-IP, mass spectrometry, surface plasmon resonance for KRAS binding; co-IP for CCT2–β-catenin–HSP105–PP2A; JAK2/STAT3 pathway readouts with IL-6 rescue; xenograft models\",\n      \"pmids\": [\"38582394\", \"38165547\", \"41789667\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Direct CCT2–STAT3 physical interaction was not demonstrated\",\n        \"Whether β-catenin stabilization requires TRiC or monomeric CCT2 is unknown\",\n        \"Structural basis for CCT2–KRAS interaction not resolved\"\n      ]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Knock-in mouse models carrying LCA mutations confirmed retinal photoreceptor degeneration and identified CCDC181 as a new CCT2-interacting protein whose ciliary localization depends on functional CCT2, extending the disease mechanism to ciliary proteostasis.\",\n      \"evidence\": \"Cct2 knock-in mice (T400P/R516H), retinal histology, co-IP for CCTβ–CCDC181, immunostaining of connecting cilia\",\n      \"pmids\": [\"38830954\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Whether CCDC181 mislocalization is sufficient to cause photoreceptor degeneration was not tested\",\n        \"Full inventory of ciliary substrates affected by CCT2 mutations was not determined\"\n      ]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Viral exploitation studies revealed that PRRSV nsp3 hijacks CCT2's aggrephagy function to degrade MDA5 aggregates, and LASV matrix protein disrupts CCT2's cytoskeletal folding to block autophagosome–lysosome fusion, demonstrating that pathogens target both arms of CCT2 biology.\",\n      \"evidence\": \"Co-IP for MDA5–CCT2–nsp3 and LASV-Z–CCT2, mutagenesis of viral interaction sites, autophagy flux assays, VLP budding assays\",\n      \"pmids\": [\"38272236\", \"39007910\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Host factor specificity—whether other TRiC subunits are similarly exploited—was not compared\",\n        \"Relevance to in vivo viral pathogenesis in animal infection models not established\"\n      ]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Discovery that CCT2 mRNA is m6A-modified by METTL3 downstream of histone lactylation revealed an epitranscriptomic axis controlling CCT2 protein levels in tumors, and elevated CCT2 suppresses CD8⁺ T cell cytotoxicity by inhibiting Ca²⁺ influx.\",\n      \"evidence\": \"ChIP for H3K18la at METTL3 locus, RIP for m6A on CCT2 mRNA, Ca²⁺ influx measurement, T cell cytotoxicity assay, homograft mouse model\",\n      \"pmids\": [\"41288742\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Direct molecular target of CCT2 that mediates Ca²⁺ channel inhibition remains unidentified\",\n        \"Whether this regulatory axis operates in non-gastric cancers was untested\"\n      ]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Identification of ALDOA as a direct CCT2 client linked chaperonin function to glycolytic reprogramming, while exosomal CCT2 was shown to polarize macrophages toward the immunosuppressive M2 phenotype, and CCT2 was separately identified as a cGAS-associated factor that attenuates cGAS-STING signaling through aggrephagy-mediated clearance of DNA-bound cGAS aggregates.\",\n      \"evidence\": \"Co-IP and GST pulldown for CCT2–ALDOA; ECAR, glucose uptake, lactate assays; exosome M2 polarization; photo-cross-linking proteomics for cGAS–CCT2; autophagy flux and STING signaling assays\",\n      \"pmids\": [\"42003909\", \"42043443\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Whether ALDOA folding requires full TRiC or monomeric CCT2 was not resolved\",\n        \"The exosomal CCT2 form (monomer vs. complex) acting on macrophages was not characterized\",\n        \"Whether cGAS aggregate clearance is specific to CCT2 or shared with other aggrephagy receptors was not tested\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Key unresolved questions include the structural basis and signals governing the TRiC-to-monomer transition, the identity of the calcium channel modulated by CCT2 in immune cells, whether CCT2's oncogenic functions require the intact chaperonin or the monomeric form, and the full client repertoire in different tissue contexts.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Structural basis for monomer release from TRiC not determined\",\n        \"Calcium channel identity downstream of CCT2 in T cells unknown\",\n        \"Systematic TRiC-dependent vs. monomer-dependent substrate classification lacking\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0044183\", \"supporting_discovery_ids\": [0, 3, 4, 5, 11, 12, 16, 17]},\n      {\"term_id\": \"GO:0140657\", \"supporting_discovery_ids\": [7]},\n      {\"term_id\": \"GO:0038024\", \"supporting_discovery_ids\": [0, 8, 10, 18]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [0, 7, 11]},\n      {\"term_id\": \"GO:0005929\", \"supporting_discovery_ids\": [4, 16]},\n      {\"term_id\": \"GO:0005576\", \"supporting_discovery_ids\": [1, 9, 17]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [0, 3, 4, 5, 7, 11, 16, 17]},\n      {\"term_id\": \"R-HSA-9612973\", \"supporting_discovery_ids\": [0, 8, 10, 12, 18]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [1, 9, 10, 18, 19]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [9, 11, 13, 15]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [4, 5, 16]}\n    ],\n    \"complexes\": [\n      \"TRiC/CCT chaperonin complex\"\n    ],\n    \"partners\": [\n      \"CCT5\",\n      \"CCT3\",\n      \"KRAS\",\n      \"ALDOA\",\n      \"CTNNB1\",\n      \"GLI1\",\n      \"CCDC181\",\n      \"TRIM21\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}