Affinage

CCT4

T-complex protein 1 subunit delta · UniProt P50991

Round 2 corrected
Length
539 aa
Mass
57.9 kDa
Annotated
2026-04-28
45 papers in source corpus 11 papers cited in narrative 11 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

CCT4 is the delta subunit of the TRiC/CCT chaperonin, an ATP-dependent chaperonin complex that folds cytoskeletal proteins and signaling clients including actin, tubulin, mLST8, STAT3, and class I HDACs (PMID:23612981, PMID:35239512, PMID:35646538). Allosteric communication through CCT4 is essential for cooperative ATP binding within the hetero-oligomeric ring, as the G345D mutation abolishes both intra- and inter-ring cooperativity and causes actin organization defects, while the C450Y mutation disrupts oligomeric assembly and causes hereditary sensory neuropathy (PMID:18272176, PMID:12874111, PMID:25124038). CCT4 also interacts with Cdc20 to modulate APC/C ubiquitin ligase activity during cell cycle progression (PMID:34732665). Independent of its role in the TRiC complex, monomeric CCT4 promotes tunneling nanotube formation and enhances microtubule dynamics, revealing a chaperonin-complex-independent cellular function (PMID:41104595).

Mechanistic history

Synthesis pass · year-by-year structured walk · 7 steps
  1. 2003 High

    Identification of CCT4 as essential for neuronal survival established that disruption of a single TRiC subunit causes tissue-specific disease, raising the question of which CCT4 property—folding capacity or oligomeric assembly—is compromised by pathogenic mutations.

    Evidence Genetic mapping and sequencing in a rat hereditary sensory neuropathy model identified the C450Y missense mutation in Cct4

    PMID:12874111

    Open questions at the time
    • Biochemical mechanism by which C450Y causes neuropathy was not resolved
    • Whether tubulin or actin misfolding drives the phenotype was not determined
  2. 2008 High

    Demonstrating that the G345D mutation in CCT4 abolishes both intra- and inter-ring allosteric cooperativity in ATP binding established CCT4 as a critical hub for communication within the chaperonin ring, explaining why single-subunit mutations collapse overall TRiC function.

    Evidence ATP binding kinetics on purified yeast CCT complex bearing the anc2-1 allele, combined with growth and actin phenotype assays

    PMID:18272176

    Open questions at the time
    • Structural basis for how G345D disrupts cooperativity was not resolved
    • Whether all CCT subunits contribute equally to allostery remains unclear
  3. 2013 High

    Showing that recombinant CCT4 alone forms functional homo-oligomeric double-ring chaperonins with ATPase and refolding activity demonstrated that the delta subunit intrinsically possesses all features needed for chaperonin function, independent of hetero-oligomeric TRiC.

    Evidence E. coli expression of human CCT4, cryo-EM of homo-oligomers, ATPase and luciferase refolding assays

    PMID:23612981

    Open questions at the time
    • Substrate range of homo-oligomeric CCT4 versus hetero-oligomeric TRiC was not compared systematically
    • Physiological relevance of homo-oligomers in vivo is unknown
  4. 2014 High

    Biochemical and EM analysis of the neuropathy-associated C450Y mutant revealed that it disrupts ring formation rather than catalytic activity per se, resolving the mechanism linking this mutation to disease.

    Evidence E. coli expression of wild-type and C450Y CCT4, sucrose gradient sedimentation, and negative-stain EM

    PMID:25124038

    Open questions at the time
    • Whether C450Y also disrupts hetero-oligomeric TRiC assembly in mammalian cells was not tested
    • Dominant versus recessive effects in heterozygous carriers not characterized
  5. 2021 Medium

    Discovery that CCT4 interacts with Cdc20 and modulates APC/C-Cdc20 activity expanded CCT4 function beyond canonical substrate folding to direct regulation of cell cycle ubiquitin ligase activity.

    Evidence Co-immunoprecipitation of CCT4-Cdc20 and knockdown-induced accumulation of APC/C substrates (securin, Bim) in hepatocellular carcinoma cells

    PMID:34732665

    Open questions at the time
    • Whether CCT4 acts on Cdc20 as a folding client or as a stoichiometric regulator is unresolved
    • Reciprocal validation and endogenous complex stoichiometry not established
    • In vivo confirmation of the CCT4-Cdc20 axis is lacking
  6. 2022 High

    Two studies defined specific folding clients of CCT4—mLST8 (linking to mTOR signaling) and STAT3—showing that CCT4-dependent proteostasis controls distinct oncogenic pathways in different cancer contexts.

    Evidence YB-1/CCT4/mLST8 axis dissected via RNA-binding, co-IP, and mouse xenograft with RNA decoys in glioblastoma; anticarin-β binding to CCT4 inhibiting STAT3 maturation in osteosarcoma PDX models

    PMID:35239512 PMID:35646538

    Open questions at the time
    • Full client repertoire of CCT4 within TRiC is not catalogued
    • Whether CCT4 is rate-limiting for mLST8 or STAT3 folding in normal physiology is unknown
  7. 2025 Medium

    Identification of a chaperonin-independent function for monomeric CCT4 in promoting tunneling nanotube formation and modulating microtubule dynamics revealed that free CCT4 has distinct cellular roles beyond the TRiC complex.

    Evidence Overexpression of oligomer-excluded GFP-CCT4 constructs with fluorescence imaging and TNT quantification in mammalian cells

    PMID:41104595

    Open questions at the time
    • Molecular target of monomeric CCT4 in TNT biogenesis is unidentified
    • Whether endogenous monomeric CCT4 levels are sufficient to drive TNT formation in vivo is unknown
    • Single-lab finding awaits independent replication

Open questions

Synthesis pass · forward-looking unresolved questions
  • A unified structural and functional model explaining how CCT4 coordinates allosteric signaling within TRiC, selects specific substrates, and performs chaperonin-independent roles as a monomer remains to be constructed.
  • No high-resolution structure of the full TRiC cycle with CCT4-specific substrate engagement
  • Relative abundance and regulation of monomeric versus oligomeric CCT4 in cells is uncharacterized
  • Whether CCT4 moonlighting functions contribute to neuropathy or cancer phenotypes is unknown

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0044183 protein folding chaperone 4 GO:0140657 ATP-dependent activity 2 GO:0098772 molecular function regulator activity 1
Localization
GO:0005829 cytosol 3
Pathway
R-HSA-162582 Signal Transduction 1 R-HSA-1640170 Cell Cycle 1
Partners
CDC20HDAC1MLST8STAT3YBX1
Complex memberships
TRiC/CCT

Evidence

Reading pass · 11 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2022 YB-1 binds the 5'UTR of CCT4 mRNA to promote CCT4 translation; CCT4 in turn promotes mLST8 folding, activating both mTORC1 and mTORC2 signaling in glioblastoma, establishing a YB-1/CCT4/mLST8/mTOR proteostasis axis. RNA-binding assays (5'UTR binding), co-immunoprecipitation, western blot, mouse xenograft model with RNA decoys, knockdown experiments The Journal of clinical investigation High 35239512
2013 Human CCT4 expressed individually in E. coli forms homo-oligomeric double-ring complexes (16-mer, ~20S) that hydrolyze ATP and function as active chaperonins, capable of refolding luciferase and suppressing γD-crystallin aggregation, demonstrating CCT4 can perform chaperonin reactions without other TRiC subunits. E. coli expression, sucrose gradient sedimentation, negative stain and cryo-electron microscopy, ATPase assay, luciferase refolding assay, γD-crystallin aggregation assay The Journal of biological chemistry High 23612981
2003 A C450Y missense mutation in rat Cct4 (delta subunit of CCT) causes autosomal recessive hereditary sensory neuropathy (mutilated foot phenotype), demonstrating that CCT4 function is required for sensory neuron survival, likely through its role in folding tubulin, actin and other cytosolic proteins. Genetic mapping, sequencing of candidate genes in rat model, pathological analysis of sensory ganglia Human molecular genetics High 12874111
2008 The G345D mutation in CCT4 (yeast anc2-1 allele) abolishes both intra-ring and inter-ring cooperative ATP binding (allostery) in the CCT chaperonin complex, and yeast bearing this mutation are temperature-sensitive with defects in actin organization, budding, and cell shape, demonstrating that allosteric communication through CCT4 is essential for CCT function in vivo. ATP binding kinetics assays on purified CCT complex, growth assays, actin structure analysis in yeast Journal of molecular biology High 18272176
2014 The C450Y mutation in CCT4 reduces soluble subunit recovery and disrupts ring formation as shown by electron microscopy of homo-oligomers, establishing that this neuropathy-associated residue is critical for proper oligomeric assembly of CCT4. E. coli expression of CCT4 homo-oligomers, sucrose gradient centrifugation, negative stain electron microscopy, substrate refolding assays The Journal of biological chemistry High 25124038
2022 The compound anticarin-β specifically binds CCT4 and inhibits CCT4-mediated STAT3 maturation/folding, impairing proteostasis in osteosarcoma cells and suppressing tumor growth in orthotopic and patient-derived xenograft models. Binding assays, CCT4 knockdown and inhibitor treatment in cancer cell lines, STAT3 folding/maturation western blot, orthotopic and PDX xenograft models Acta pharmaceutica Sinica. B Medium 35646538
2021 CCT4 interacts with Cdc20 to modulate APC/C-Cdc20 ubiquitin ligase activity; CCT4 knockdown causes accumulation of APC/C-Cdc20 substrates securin and Bim, leading to downregulation of cyclin D1, activation of caspase 9, and induction of apoptosis in hepatocellular carcinoma cells. Co-immunoprecipitation, shRNA knockdown, western blot, CCK-8 and EdU proliferation assays, flow cytometry apoptosis assay Chinese medical journal Medium 34732665
2022 CCT4 knockdown in esophageal squamous cell carcinoma cells raises oxidative stress, inhibits glycolysis, and sensitizes cells to cisplatin via modulation of the AMPK/AKT/Nrf2 signaling pathway. CCT4 shRNA knockdown, glycolysis assays, ROS measurement, drug sensitivity assays, western blot for AMPK/AKT/Nrf2 pathway components Molecular carcinogenesis Low 36102200
2025 Monomeric CCT4 (not incorporated into the TRiC oligomer) promotes tunneling nanotube (TNT) formation in mammalian cultured cells; GFP-CCT4 that cannot join the chaperonin complex induces thick nanotubes containing actin fibers and mitochondria, enhances microtubule dynamics, and increases tubulin-containing TNTs, identifying a chaperonin-independent function of CCT4. GFP-CCT4 overexpression constructs (oligomer-excluded forms), fluorescence microscopy, TNT quantification, microtubule dynamics imaging FEBS letters Medium 41104595
2025 Cryo-EM structural analysis of TRiC-HDAC1 complex reveals an unexpected bent conformation of CCT4 within the complex that may facilitate co-chaperone dissociation from TRiC during HDAC1 folding. Cryo-EM, cross-linking mass spectrometry, biochemistry bioRxivpreprint Medium bio_10.1101_2025.05.21.655272
2023 lncCCT4-2 delivered via propofol-treated endothelial cell-derived microvesicles stabilizes CCT4 mRNA (shown by actinomycin D assay) and promotes CCT4 protein expression in cardiomyocytes, thereby inhibiting oxidative stress and apoptosis in ischemia-reperfusion injury. RNA sequencing of microvesicles, RT-qPCR, actinomycin D mRNA stability assay, lentiviral lncCCT4-2 knockdown, CCT4 plasmid overexpression/knockdown, in vitro HR model and in vivo mouse cardiac IR model Biological research Medium 37143143

Source papers

Stage 0 corpus · 45 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2012 Insights into RNA biology from an atlas of mammalian mRNA-binding proteins. Cell 1718 22658674
2002 Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences. Proceedings of the National Academy of Sciences of the United States of America 1479 12477932
2015 The BioPlex Network: A Systematic Exploration of the Human Interactome. Cell 1118 26186194
2017 Architecture of the human interactome defines protein communities and disease networks. Nature 1085 28514442
2015 A human interactome in three quantitative dimensions organized by stoichiometries and abundances. Cell 1015 26496610
2020 A reference map of the human binary protein interactome. Nature 849 32296183
2004 A physical and functional map of the human TNF-alpha/NF-kappa B signal transduction pathway. Nature cell biology 841 14743216
2018 VIRMA mediates preferential m6A mRNA methylation in 3'UTR and near stop codon and associates with alternative polyadenylation. Cell discovery 829 29507755
2021 Dual proteome-scale networks reveal cell-specific remodeling of the human interactome. Cell 705 33961781
2012 A census of human soluble protein complexes. Cell 689 22939629
2015 Gene essentiality and synthetic lethality in haploid human cells. Science (New York, N.Y.) 657 26472760
2011 Phylogenetic-based propagation of functional annotations within the Gene Ontology consortium. Briefings in bioinformatics 656 21873635
2018 High-Density Proximity Mapping Reveals the Subcellular Organization of mRNA-Associated Granules and Bodies. Molecular cell 580 29395067
2006 Hsp90 cochaperone Aha1 downregulation rescues misfolding of CFTR in cystic fibrosis. Cell 517 17110338
2003 Exploring proteomes and analyzing protein processing by mass spectrometric identification of sorted N-terminal peptides. Nature biotechnology 485 12665801
2004 The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC). Genome research 438 15489334
2015 A Dynamic Protein Interaction Landscape of the Human Centrosome-Cilium Interface. Cell 433 26638075
2022 OpenCell: Endogenous tagging for the cartography of human cellular organization. Science (New York, N.Y.) 432 35271311
2013 The intracellular interactome of tetraspanin-enriched microdomains reveals their function as sorting machineries toward exosomes. The Journal of biological chemistry 413 23463506
2005 Diversification of transcriptional modulation: large-scale identification and characterization of putative alternative promoters of human genes. Genome research 409 16344560
2015 Panorama of ancient metazoan macromolecular complexes. Nature 407 26344197
2005 Human ISG15 conjugation targets both IFN-induced and constitutively expressed proteins functioning in diverse cellular pathways. Proceedings of the National Academy of Sciences of the United States of America 383 16009940
1996 Generation and analysis of 280,000 human expressed sequence tags. Genome research 376 8889549
2015 Proteome-wide profiling of protein assemblies by cross-linking mass spectrometry. Nature methods 370 26414014
2007 Systematic analysis of the protein interaction network for the human transcription machinery reveals the identity of the 7SK capping enzyme. Molecular cell 367 17643375
2021 A proximity-dependent biotinylation map of a human cell. Nature 339 34079125
2011 Acetylation regulates gluconeogenesis by promoting PEPCK1 degradation via recruiting the UBR5 ubiquitin ligase. Molecular cell 337 21726808
2010 Dynamics of cullin-RING ubiquitin ligase network revealed by systematic quantitative proteomics. Cell 318 21145461
2008 A PP2A phosphatase high density interaction network identifies a novel striatin-interacting phosphatase and kinase complex linked to the cerebral cavernous malformation 3 (CCM3) protein. Molecular & cellular proteomics : MCP 302 18782753
2012 A high-throughput approach for measuring temporal changes in the interactome. Nature methods 273 22863883
2022 Upregulated YB-1 protein promotes glioblastoma growth through a YB-1/CCT4/mLST8/mTOR pathway. The Journal of clinical investigation 56 35239512
2013 Human CCT4 and CCT5 chaperonin subunits expressed in Escherichia coli form biologically active homo-oligomers. The Journal of biological chemistry 55 23612981
2003 Hereditary sensory neuropathy is caused by a mutation in the delta subunit of the cytosolic chaperonin-containing t-complex peptide-1 (Cct4 ) gene. Human molecular genetics 49 12874111
2008 ATP-induced allostery in the eukaryotic chaperonin CCT is abolished by the mutation G345D in CCT4 that renders yeast temperature-sensitive for growth. Journal of molecular biology 46 18272176
2014 Biochemical characterization of mutants in chaperonin proteins CCT4 and CCT5 associated with hereditary sensory neuropathy. The Journal of biological chemistry 29 25124038
2022 Anticarin-β shows a promising anti-osteosarcoma effect by specifically inhibiting CCT4 to impair proteostasis. Acta pharmaceutica Sinica. B 23 35646538
2021 CCT4 suppression inhibits tumor growth in hepatocellular carcinoma by interacting with Cdc20. Chinese medical journal 17 34732665
2022 CCT4 knockdown enhances the sensitivity of cisplatin by inhibiting glycolysis in human esophageal squamous cell carcinomas. Molecular carcinogenesis 12 36102200
2024 LINC01234 promoted malignant behaviors of breast cancer cells via hsa-miR-30c-2-3p/CCT4/mTOR signaling pathway. Taiwanese journal of obstetrics & gynecology 8 38216268
2023 Role of CCT4/ErbB signaling in nephroblastoma: Implications for a biomarker of Wilms tumor. Medicine 6 37058032
2023 Propofol inhibits myocardial injury induced by microvesicles derived from hypoxia-reoxygenated endothelial cells via lncCCT4-2/CCT4 signaling. Biological research 5 37143143
1995 Cloning and sequencing of the chaperonin-encoding Cctd gene from Fugu rubripes rubripes. Gene 5 8543170
1996 Chromosomal assignment and imprinting tests for the mouse delta subunit of the cytosolic chaperonin containing TCP-1 (Cct4) gene to proximal chromosome 11. Genomics 2 8661059
2025 CCT4 promotes tunneling nanotube formation. FEBS letters 0 41104595
2025 Pan-cancer multi-omics analysis of CCT4 in tumor progression and cancer immunity, with focus on lung adenocarcinoma. Frontiers in immunology 0 41403933