| 2022 |
CCT2 functions as an autophagy receptor (aggrephagy receptor) for solid protein aggregates by associating with aggregation-prone proteins independent of ubiquitination and interacting with autophagosome marker ATG8s through a non-classical VLIR motif. Aggregation-prone protein accumulation induces a functional switch of CCT2 from a chaperonin subunit to an autophagy receptor by promoting CCT2 monomer formation, which exposes the VLIR motif for ATG8 interaction. |
Co-immunoprecipitation, in vitro binding assays, mutagenesis of VLIR motif, live-cell imaging, mouse brain model, comparison with ubiquitin-binding receptors P62/NBR1/TAX1BP1 |
Cell |
High |
35366418
|
| 2022 |
CCT2-mediated aggrephagy specifically promotes autophagic degradation of solid protein aggregates (low liquidity) but not liquid condensates, and operates independently of the ubiquitin-binding receptors P62, NBR1, and TAX1BP1, and independently of chaperone-mediated autophagy. |
Genetic knockdown/knockout with phenotypic readout comparing aggregate vs. condensate clearance; comparison with other receptor mutants |
Cell |
High |
35366418
|
| 2024 |
Atg1 (ULK1 ortholog) phosphorylates CCT2 at Ser412 and Ser470; disruption of these phosphorylation sites impairs solid aggrephagy by hindering CCT2-Atg8 binding. Additionally, adaptor protein Atg11 directly associates with CCT2 through its CC4 domain, and this interaction is required for CCT2-Atg8 binding and efficient aggrephagy. Both mechanisms are conserved in mammalian cells. |
In vitro kinase assay, phosphosite mutagenesis, Co-IP, domain mapping, yeast and mammalian cell assays |
EMBO reports |
High |
39322741
|
| 2023 |
The LCA-associated double mutation T400P/R516H in CCT2 (corresponding to T394P/R510H in yeast) reduces the off-rate of ADP during ATP hydrolysis by the CCT/TRiC complex, stabilizing its closed state and thereby impeding the exit of CCT2 monomers from the complex required for autophagy function. ATPase activity of CCT/TRiC is stimulated by non-folded substrate. |
Steady-state and transient kinetic analysis of ATPase activity in yeast CCT/TRiC with disease-mimicking mutations |
Communications biology |
High |
37644231
|
| 2016 |
LCA-causative mutations T400P and R516H in CCT2 destabilize the chaperonin complex and impair affinity for adjacent subunit CCTγ. CCT2 knockdown reduces the major client protein transducin β1 (Gβ1), and wild-type but not mutant CCT2 rescues proliferation defects in Cct2-knockdown cells. |
Biochemical stability assays, Co-IP for subunit interactions, Cct2 knockdown in 661W cells with rescue by wild-type vs. mutant expression, patient-derived iPSCs |
Scientific reports |
Medium |
27645772
|
| 2018 |
In zebrafish, loss of cct2 (L394H-7del CRISPR mutation) leads to reduced levels of client protein Gβ1, attenuated retinal ganglion cell differentiation, disrupted cell cycle, and increased retinal cell death. Injection of wild-type human CCTβ RNA rescues the small eye phenotype and restores Gβ1 levels, confirming CCT2's role in folding Gβ1 and retinal development. |
CRISPR-Cas9 knockout zebrafish, immunostaining, TUNEL, EdU assay, RNA rescue injection, western blot for client protein |
Investigative ophthalmology & visual science |
High |
29450543
|
| 2024 |
CCT2 directly binds to KRAS (shown by co-immunoprecipitation, mass spectrometry, and surface plasmon resonance), leading to increased KRAS protein stability and upregulated downstream KRAS signaling in glioblastoma. Dihydroartemisinin directly binds CCT2 and reduces KRAS expression; CCT2 overexpression rescues the inhibitory effect of dihydroartemisinin on glioblastoma. |
Co-immunoprecipitation, mass spectrometry, surface plasmon resonance, overexpression rescue assay, in vivo glioblastoma animal model |
Cancer letters |
Medium |
38582394
|
| 2019 |
Under hypoxia, CCT2 interacts with Gli-1 (a Hedgehog signaling transcription factor) as identified by mass spectrometry. CCT2 depletion inhibits tumor induction by Gli-1, and CCT2 assists in Gli-1 folding to prevent ubiquitination-mediated Gli-1 degradation by β-TrCP in colorectal cancer cells. |
Mass spectrometry, western blotting, immunofluorescence, siRNA knockdown, xenograft model |
Oncogene |
Medium |
31462707
|
| 2019 |
CCT2 (and CCT5) are required for stabilization of Cdc20, and depletion of CCT2 reduces Cdc20 levels and reverses Muscovy duck reovirus p10.8-mediated CDK4 degradation and apoptosis, placing CCT2 upstream of Cdc20 in cell cycle and apoptosis regulation. |
siRNA knockdown, western blot, apoptosis assay, cell cycle analysis |
Veterinary microbiology |
Medium |
31282373
|
| 2024 |
PRRSV nsp3 enhances the interaction between porcine MDA5 and CCT2, promoting aggregate formation and autophagic clearance of MDA5-CCT2-nsp3 complexes independently of ubiquitination, thereby suppressing innate immune signaling. |
Co-immunoprecipitation, autophagy flux assays, siRNA knockdown, western blot |
Virologica Sinica |
Medium |
38272236
|
| 2024 |
Lassa virus matrix protein Z interacts with CCT2 (via residues Q29 and Y48 on LASV-Z), blocking actin and tubulin folding, disrupting the cytoskeleton, and preventing autophagosome-lysosome fusion, leading to autophagosome accumulation that promotes viral particle budding. |
Co-immunoprecipitation, site-directed mutagenesis, fluorescence microscopy for autophagosome-lysosome fusion, VLP budding assay |
Autophagy |
Medium |
39007910
|
| 2024 |
E3 ubiquitin ligase Trim21 facilitates CCT2 ubiquitination and degradation, reversing CCT2's pro-tumorigenic effects in breast cancer. CCT2 promotes breast cancer growth and metastasis through activation of the JAK2/STAT3 signaling pathway. Exosomal CCT2 from breast cancer cells suppresses CD4+ T cell activation by constraining Ca2+-NFAT1 signaling and reducing CD40L expression. |
Co-immunoprecipitation, ubiquitination assay, knockdown/overexpression with downstream signaling readout (JAK2/STAT3 phosphorylation), exosome isolation and T cell co-culture assay |
Cell death & disease |
Medium |
39079960
|
| 2020 |
CCT2 enriched in UC-MSC-derived extracellular vesicles regulates calcium channels to affect Ca2+ influx, suppressing CD154 (CD40L) synthesis in CD4+ T cells via the Ca2+-calcineurin-NFAT1 signaling pathway, thereby modulating the inflammatory response in liver ischemia/reperfusion injury. |
Protein mass spectrometry of EV contents, Ca2+ flux measurement, western blot for NFAT1/calcineurin pathway components, in vivo mouse liver IRI model |
Advanced science |
Medium |
32999825
|
| 2024 |
CCT2 prevents β-catenin proteasomal degradation in epithelial ovarian cancer by recruiting the HSP105-PP2A dephosphorylation complex to β-catenin via direct physical interaction, preventing phosphorylation-induced proteasomal degradation and causing intracellular accumulation of active β-catenin and increased Wnt signaling. |
Co-IP assays, ubiquitin assays, western blot for β-catenin phosphorylation, knockdown/overexpression with Wnt target readout |
Molecular biology reports |
Medium |
38165547
|
| 2024 |
CCT2 is required for ciliogenesis: knockdown of CCT2 reduces the number of ciliated cells and results in shorter primary cilia. CCT2, as part of a TRiC/CCT-BBS chaperonin co-complex, is required for the localization of the adhesion GPCR ADGRV1 to the base of primary cilia; in the absence of CCT2, ADGRV1 is depleted from the ciliary base and degraded via the proteasome. |
siRNA knockdown with ciliogenesis phenotyping, immunofluorescence localization, co-complex pulldown, proteasome inhibitor rescue assay |
bioRxivpreprint |
Medium |
bio_10.1101_2024.10.31.621306
|
| 2025 |
CCT2 recruits TRIM28 to catalyze SUMO2 modification of TMX1, inhibiting TMX1 ubiquitination and enhancing TMX1 protein stability, which promotes TMX1-dependent ROS clearance and confers resistance to third-generation EGFR-TKIs in non-small cell lung cancer. |
CRISPR/Cas9 genome-wide screen, TMT proteomic analysis, Co-IP, SUMOylation and ubiquitination assays, ROS measurement, xenograft models |
Cell death and differentiation |
Medium |
41168408
|
| 2026 |
CCT2 directly interacts with and stabilizes the glycolytic enzyme ALDOA (aldolase A) in hepatocellular carcinoma, as shown by co-immunoprecipitation and GST pulldown, resulting in increased glycolytic activity (extracellular acidification rate, glucose uptake, lactate production). |
Co-immunoprecipitation, GST pulldown, extracellular acidification rate measurement, glucose uptake and lactate assays, metabolomic profiling |
International journal of biological sciences |
Medium |
42003909
|
| 2026 |
CCT2 transcription is upregulated by transcription factor FOXA1; CCT2 interacts with EIF3F and FASN to form a ternary CCT2/EIF3F/FASN complex that enhances EIF3F-mediated deubiquitination of FASN, increasing FASN protein stability and lipid synthesis in prostate cancer. |
ChIP for FOXA1-CCT2 promoter binding, Co-IP for ternary complex, ubiquitination assay for FASN, lipid synthesis assays, in vivo xenograft and PDX models |
Advanced science |
Medium |
42231807
|
| 2026 |
CCT2 facilitates autophagy-mediated turnover of DNA-bound cGAS aggregates (cGAS-DNA condensates), thereby attenuating cGAS-STING innate immune signaling. CCT2 was identified as a cGAS-associated factor using site-specific photo-cross-linking coupled with quantitative proteomics. |
Residue-resolved photo-cross-linking, quantitative proteomics, autophagy flux assays, cGAS-STING reporter assays |
ACS chemical biology |
Medium |
42043443
|
| 2024 |
In a mouse model, the CCT2 R516H homozygous mutation causes photoreceptor degeneration with significant depletion of TRiC/CCT substrate proteins in the retina, while T400P homozygosity causes embryonic lethality. CCDC181 was identified as an interacting protein for CCTβ, and its localization to photoreceptor connecting cilia is compromised in the compound heterozygous T400P/R516H mutant mouse. |
Knock-in mouse model, retinal histology, western blot for substrate proteins, Co-IP for CCDC181 interaction, immunofluorescence for ciliary localization |
Communications biology |
Medium |
38830954
|