CCT6A

CCT6A (Tcp20) is the zeta subunit of the eukaryotic TRiC/CCT chaperonin, a hetero-oligomeric complex required for ATP-dependent folding of cytoplasmic proteins, and its gene is essential in yeast (PMID:8034610). It is broadly expressed across mammalian tissues with ATP-binding sites conserved from yeast to mammals, consistent with this folding role (PMID:10810232). Beyond the canonical chaperonin function, CCT6A acts in cancer as a direct protein-binding partner that rewires signaling: it binds SMAD2 and selectively inhibits SMAD2 function, switching TGF-β-induced transcription toward a prometastatic program in non-small-cell lung carcinoma (PMID:28375158), and it binds STAT1 to protect it from ubiquitin-mediated degradation, stabilizing STAT1 to drive transcription of hexokinase 2 (HK2) and aerobic glycolysis (PMID:38750462). CCT6A also directly binds both wild-type and mutant p53 to regulate BIRC5/survivin through p53-dependent and p53-independent routes (PMID:38997438). CCT6A protein levels are controlled by the E3 ligase TRIM38, which directly binds CCT6A and catalyzes K48-linked ubiquitination at K127/K138 to target it for proteasomal degradation; loss of CCT6A reduces c-Myc stabilization and suppresses the MYC pathway (PMID:40047371). CCT6A is secreted via exosomes from stromal and tumor cells, where transferred CCT6A interacts with β-catenin to promote its nuclear translocation and c-Myc-driven transcriptional programs supporting stemness, chemoresistance, and glycolysis (PMID:40801472).

1. 1994 High

   Established that CCT6A is a bona fide subunit of the TRiC/CCT chaperonin and that the gene is essential, defining its foundational role in cytoplasmic protein folding.

   Evidence Gel filtration plus Western blotting of purified bovine testis TRiC with a Tcp20-specific antibody, and yeast TCP20 gene disruption

   PMID:8034610

   Open questions at the time

   • Does not map which client proteins depend on the CCT6A subunit specifically
   • No structural detail on CCT6A's position within the ring
2. 2000 Medium

   Showed CCT6A is widely expressed and its ATP-binding sites are evolutionarily conserved, supporting a general role in ATP-dependent folding across mammalian tissues.

   Evidence Western blotting with anti-human CCT6 antibody across tissues; cDNA cloning and sequence analysis

   PMID:10810232

   Open questions at the time

   • Expression survey does not demonstrate tissue-specific function
   • ATP-binding sites inferred from sequence, not measured biochemically
3. 2013 Medium

   Identified hormonal transcriptional control of CCT6A, with progesterone activating and FSH inhibiting its expression via a defined promoter element.

   Evidence Promoter deletion and site-directed mutagenesis reporter assays in chicken granulosa cells

   PMID:23644154

   Open questions at the time

   • Performed in chicken granulosa cells; mammalian relevance not established
   • Functional consequence of CCT6A induction not assayed
4. 2017 High

   Defined a non-canonical CCT6A function as a direct SMAD2 binder that selectively inhibits SMAD2 to redirect TGF-β signaling toward metastasis, distinguishing it from a pure folding role.

   Evidence Reciprocal Co-IP, NSCLC cell lines, animal metastasis models, and clinical specimens with selective SMAD3/CCT6A inhibition

   PMID:28375158

   Open questions at the time

   • Does not resolve how CCT6A discriminates SMAD2 from SMAD3
   • Relationship of this moonlighting role to the TRiC complex unclear
5. 2022 Medium

   Placed CCT6A downstream of HOXB2 in a transcriptional axis driving colon cancer progression, establishing an upstream regulator of CCT6A expression.

   Evidence ChIP and luciferase reporter for direct HOXB2 promoter binding; CCT6A knockdown and HOXB2 overexpression

   PMID:35315492

   Open questions at the time

   • Single lab
   • Does not connect HOXB2-driven CCT6A to a specific downstream effector mechanism
6. 2023 Low

   Linked CCT6A to TGF-β/Smad/c-Myc pathway activation and EMT in esophageal carcinoma, extending the TGF-β connection to a new tumor type.

   Evidence siRNA knockdown/overexpression with TGF-β rescue and Western blot for p-Smad2/3 and c-Myc in ESCC cells

   PMID:37017854

   Open questions at the time

   • Pathway activation inferred from downstream markers without direct binding evidence
   • Apparent contrast with SMAD2-inhibitory model not reconciled
7. 2024 Medium

   Expanded CCT6A's interactome to STAT1 and p53, showing it stabilizes STAT1 to drive HK2-dependent glycolysis and binds both wild-type and mutant p53 to regulate survivin.

   Evidence Co-IP, ChIP, transcriptomics and LC-MS in lung adenocarcinoma; Co-IP and p53-status-dependent functional readouts in colon cancer

   PMID:38750462 PMID:38997438

   Open questions at the time

   • Mechanism by which CCT6A shields STAT1 from ubiquitination not defined
   • No structural basis for distinct wild-type vs mutant p53 handling
8. 2024 Low

   Connected CCT6A to glycolysis and metastasis through additional partners (TCAB1/TERT axis, RPS3), broadening its metabolic-rewiring role across tumor types.

   Evidence Co-IP and HK2 promoter assays with xenografts in cervical cancer; Co-IP and migration/invasion assays in HCC

   PMID:38657573 PMID:39630318

   Open questions at the time

   • RPS3 link rests on a single Co-IP with unresolved mechanism
   • Whether these converge on a common glycolytic program is untested
9. 2025 High

   Identified TRIM38 as the E3 ligase that directly ubiquitinates CCT6A at K127/K138 for proteasomal degradation, providing the first defined mechanism controlling CCT6A protein turnover and its downstream c-Myc stabilization.

   Evidence Co-IP, ubiquitination assays, K127/K138 mutagenesis, and in vivo tumor suppression in colorectal cancer

   PMID:40047371

   Open questions at the time

   • Signals that activate TRIM38-mediated CCT6A degradation unknown
   • Mechanism by which CCT6A stabilizes c-Myc not defined
10. 2025 Medium

    Established CCT6A as an exosome-transferable factor that acts cell-non-autonomously, binding β-catenin to drive nuclear translocation and shuttling chemokines to reprogram the tumor microenvironment.

    Evidence CAF–cancer cell co-culture and exosomal transfer, Co-IP for β-catenin and chemokine interactions, nuclear fractionation, and in vivo macrophage polarization assays

    PMID:40374617 PMID:40801472

    Open questions at the time

    • Mechanism of CCT6A loading into exosomes unknown
    • Single lab for each tumor context

• How CCT6A's canonical TRiC folding function relates mechanistically to its many moonlighting protein-binding and secreted activities remains unresolved.
• No structural account of how a chaperonin subunit engages SMAD2, STAT1, p53, and β-catenin
• Whether moonlighting functions require free CCT6A versus assembled TRiC is untested
• Mechanism directing CCT6A secretion into exosomes is undefined