cct-8 encodes the theta (CCT-theta / TCP-1-theta) subunit of the eukaryotic cytosolic chaperonin CCT (chaperonin-containing TCP-1), also known as TRiC. CCT/TRiC is an ATP-dependent, hetero-oligomeric double-ring chaperonin whose two rings are each built from eight distinct but paralogous subunits (CCT1-CCT8 / alpha-theta); cct-8 is the theta paralog. The assembled complex, not any individual subunit, is the folding machine: it uses cycles of ATP binding and hydrolysis by its subunits to fold roughly a tenth of the cytosolic proteome, most notably the obligate cytoskeletal substrates actin and tubulin, as well as WD40 beta-propeller proteins. The theta subunit contributes an equatorial nucleotide-binding module and an apical substrate-binding surface; it is one of the low-ATPase subunits and participates in substrate contacts and in allosteric coordination of the folding cycle. In C. elegans, cct-8 acts in the cytoplasm, is required for correct subcellular localization of the germ-granule protein PGL-1, and is a limiting determinant of TRiC/CCT assembly: raising CCT8 levels increases assembled chaperonin, suppresses aggregation of polyglutamine and mutant Huntingtin proteins, and extends lifespan, so cct-8 supports cytosolic protein homeostasis during aging and in the germline.
Definition: A molecular function of a single subunit of a group II chaperonin (CCT/TRiC) that presents an apical-domain substrate-binding surface and contributes subunit-specific contacts to the ATP-dependent folding of client proteins by the assembled chaperonin, without itself folding a substrate independently of the complex.
Justification: Individual CCT subunits have no adequate GO molecular-function term and can only be annotated with the complex-level foldase activity or a generic catalytic term, obscuring subunit-specific substrate selectivity.
Parent term: molecular_function
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
|
GO:0006457
protein folding
|
IBA
GO_REF:0000033 |
ACCEPT |
Summary: cct-8 is the theta subunit of the cytosolic chaperonin CCT/TRiC, which catalyzes ATP-dependent folding of cytoskeletal and other cytosolic substrates. Protein folding is the core biological process for this subunit.
Reason: The phylogenetic (IBA) inference is fully consistent with the conserved chaperonin family assignment (PANTHER PTHR11353; InterPro theta-subunit signatures) and with direct biochemical demonstration that purified CCT catalyzes actin folding. In C. elegans, raising CCT8 levels increases assembled TRiC/CCT and suppresses protein aggregation, confirming the folding role in vivo.
Supporting Evidence:
PMID:16762366
The eukaryotic cytosolic chaperonin CCT is an essential ATP-dependent protein folding machine whose action is required for folding the cytoskeletal proteins actin and tubulin
PMID:27892468
increased TRiC/CCT complex is required to avoid aggregation of mutant Huntingtin protein
file:interpro/panther/PTHR11353/PTHR11353-metadata.yaml
CHAPERONIN
|
|
GO:0005832
chaperonin-containing T-complex
|
IBA
GO_REF:0000033 |
ACCEPT |
Summary: cct-8 is an integral subunit of the chaperonin-containing T-complex (CCT/TRiC), which is built from eight paralogous subunits per ring.
Reason: The CCT complex is assembled from a stoichiometric array of subunits Cct1p-Cct8p; cct-8 is the theta subunit. In C. elegans, ectopic CCT8 is rate-limiting for assembly of the complex. Complex membership is the most important and best-supported annotation for this gene.
Supporting Evidence:
PMID:15704212
Eukaryotic chaperonins, the Cct complexes, are assembled into two rings, each of which is composed of a stoichiometric array of eight different subunits, which are denoted Cct1p-Cct8p.
PMID:27892468
ectopic expression of a single subunit (CCT8) is sufficient to increase TRiC/CCT assembly
|
|
GO:0005524
ATP binding
|
IEA
GO_REF:0000002 |
ACCEPT |
Summary: Each CCT subunit binds ATP/ADP through the conserved equatorial nucleotide-binding site of the group II chaperonin fold; nucleotide binding is integral to the folding cycle.
Reason: ATP binding is a conserved, well-established property of CCT/TRiC subunits, consistent with the InterPro chaperonin domains and the ATP-dependent mechanism of the complex. The theta subunit is a low-ATPase subunit that binds and retains nucleotide, so ATP binding is the most accurate concrete molecular-function annotation for it.
Supporting Evidence:
PMID:16762366
The eukaryotic cytosolic chaperonin CCT is an essential ATP-dependent protein folding machine
|
|
GO:0005737
cytoplasm
|
IEA
GO_REF:0000120 |
ACCEPT |
Summary: CCT/TRiC is a cytosolic chaperonin; cct-8 acts in the cytoplasm on cytosolic substrates.
Reason: Cytoplasmic localization is consistent with the known biology of the cytosolic chaperonin and with the UniProt subcellular location. The more specific term cytosol (GO:0005829) would be preferable, but the broader cytoplasm annotation is not incorrect and is retained.
Supporting Evidence:
PMID:16762366
The eukaryotic cytosolic chaperonin CCT
|
|
GO:0006457
protein folding
|
IEA
GO_REF:0000002 |
ACCEPT |
Summary: InterPro domain-based annotation of protein folding, duplicating the IBA protein-folding annotation.
Reason: Consistent electronic (InterPro) support for the core protein-folding process, in agreement with the IBA annotation and the conserved chaperonin mechanism.
Supporting Evidence:
PMID:16762366
Yeast CCT catalyses the folding of yeast ACT1p and human beta-actin with nearly identical rate constants and yields.
|
|
GO:0016887
ATP hydrolysis activity
|
IEA
GO_REF:0000002 |
ACCEPT |
Summary: The CCT subunits form ATPases; ATP hydrolysis around the ring powers the substrate-folding cycle of the chaperonin.
Reason: ATP hydrolysis is a conserved catalytic activity of the CCT/TRiC family, supported by the InterPro chaperonin domains. This is a family-level electronic annotation; the theta subunit specifically is one of the low-ATPase subunits that retains bound ADP, but it preserves the catalytic P-loop and aspartate, so the term is retained rather than removed.
Supporting Evidence:
PMID:16762366
The eukaryotic cytosolic chaperonin CCT is an essential ATP-dependent protein folding machine
file:worm/cct-8/cct-8-deep-research-falcon.md
CCT-8 occupies a defined position in the low-ATPase hemisphere and plays a specialized role in substrate binding, allosteric regulation, and complex assembly
|
|
GO:0140662
ATP-dependent protein folding chaperone
|
IEA
GO_REF:0000002 |
ACCEPT |
Summary: ATP-dependent protein folding chaperone is the most informative molecular-function term for CCT/TRiC; cct-8 contributes to this activity as a subunit of the complex.
Reason: This term precisely captures the activity of the CCT chaperonin. Strictly it is a complex-level activity to which the theta subunit contributes rather than one it enables alone, but the annotation is appropriate and is the best available molecular-function descriptor for this gene.
Supporting Evidence:
PMID:16762366
The eukaryotic cytosolic chaperonin CCT is an essential ATP-dependent protein folding machine
|
Q: Which native C. elegans clients depend specifically on the theta (cct-8) subunit contacts, as opposed to the CCT/TRiC complex as a whole?
Q: Is PGL-1 a direct CCT/TRiC substrate, or is its P-granule mislocalization on cct-8 depletion an indirect consequence of impaired actin/tubulin folding?
Q: Is the low-ATPase, substrate-binding character of the theta subunit seen in mammalian/yeast CCT structures conserved and functionally important in C. elegans?
Experiment: Perform affinity purification/mass spectrometry of tagged cct-8 (or the assembled CCT/TRiC) from C. elegans to identify native clients, and test whether PGL-1 co-purifies with the chaperonin.
Hypothesis: cct-8 engages a defined set of native C. elegans clients that includes cytoskeletal proteins and may include germ-granule components.
Experiment: Map theta-subunit apical-domain substrate contacts by crosslinking mass spectrometry or cryo-EM of CCT/TRiC caught with folding substrates, to define the subunit-specific substrate-binding contribution.
Hypothesis: The theta apical domain makes distinct substrate contacts that differ from the other seven CCT subunits.
What is not known — curated, literature-grounded statements of the open unknowns (the inverse of core functions).
Gap: The native C. elegans client repertoire that specifically depends on the theta (CCT8) subunit is undefined, and there is no GO molecular-function term that expresses "substrate-binding subunit of the CCT chaperonin". The theta subunit's own activity can therefore only be annotated as the complex-level foldase (GO:0140662) or as generic ATP binding/hydrolysis, leaving cct-8 molecular-function-dark at the subunit level.
OPEN ONTOLOGYBIOLOGY MF_DARK
What is known: It is firmly established that cct-8 is the theta subunit of the eight-membered CCT/TRiC ring, that the assembled complex folds actin, tubulin, WD40 proteins, and about 10% of the cytosolic proteome, and that the eight subunits are functionally non-equivalent. Structural work in CCT/TRiC further shows theta is a low-ATPase subunit that makes substrate contacts (actin and tubulin contact CCT8-containing apical domains) and contributes to allostery and assembly.
Significance: CCT subunits are individually essential and non-redundant, so subunit-specific substrate engagement underlies the complex's client selectivity. Because no ontology term names a chaperonin substrate-binding subunit activity, the theta subunit's characterized structural/regulatory role cannot be curated, and its native worm-specific clients remain unmapped.
What would resolve it: Affinity-proteomics of the C. elegans CCT/TRiC to define native theta clients, plus crosslinking or cryo-EM mapping of theta apical-domain contacts, would define the subunit contribution; a new GO molecular-function term for a chaperonin substrate-binding subunit activity would let the knowledge be expressed.
Provenance (the field's own admissions):
Proposed term (ontology gap):
Gap: It is unknown whether the germ-granule protein PGL-1 is a direct CCT/TRiC client of cct-8 or whether the pgl-1 mislocalization seen on cct-8 depletion is an indirect consequence of impaired folding of another substrate (for example actin, which scaffolds germ granules).
OPEN BIOLOGY RESIDUAL_SUBGAP
What is known: cct-8 depletion causes low, diffuse PGL-1 localization in C. elegans embryos rather than confinement to granules, and cct-8 knockdown promotes neuronal polyglutamine aggregation, identifying cct-8 as required for correct protein solubility/localization in vivo. Whether PGL-1 physically engages the chaperonin has not been tested.
Significance: Distinguishing a direct chaperonin-client relationship from an indirect cytoskeletal effect would clarify how the general folding machinery supports germline biomolecular-condensate (P-granule) assembly.
What would resolve it: Test whether PGL-1 physically engages CCT/TRiC (co-purification, in vitro folding assays) and whether actin/tubulin folding defects alone reproduce the P-granule phenotype.
Provenance (the field's own admissions):
The research report should be a detailed narrative explaining the function, biological processes, and localization of the gene product. Citations should be given for all claims.
You should prioritize authoritative reviews and primary scientific literature when conducting research. You can supplement
this with annotations you find in gene/protein databases, but these can be outdated or inaccurate.
We are specifically interested in the primary function of the gene - for enzymes, what reaction is catalyzed, and what is the substrate specificity? For transporters, what is the substrate? For structural proteins or adapters, what is the broader structural role? For signaling molecules, what is the role in the pathway.
We are interested in where in or outside the cell the gene product carries out its function.
We are also interested in the signaling or biochemical pathways in which the gene functions. We are less interested in broad pleiotropic effects, except where these elucidate the precise role.
Include evidence where possible. We are interested in both experimental evidence as well as inference from structure, evolution, or bioinformatic analysis. Precise studies should be prioritized over high-throughput, where available.
The C. elegans gene cct-8 (ORF name Y55F3AR.3; UniProt Q9N358) encodes the theta (θ) subunit of the eukaryotic group II chaperonin known as TRiC (TCP-1 Ring Complex), also designated CCT (chaperonin containing TCP-1). CCT-8 belongs to the TCP-1 chaperonin family and contains the characteristic domain architecture of the CCT/GroEL superfamily, including the Cpn60/TCP-1 equatorial domain (ATP-binding), an intermediate hinge domain, and the apical substrate-binding domain (Chap_CCT_theta, IPR012721) (smith2022mechanisticinsightsinto pages 1-3, willison2018thesubstratespecificity pages 1-2). The protein is conserved across eukaryotes, with clear orthologs in yeast (CCT8), mammals (CCT8/CCTθ), and other organisms (brackley2009activitiesofthe pages 1-2).
CCT-8 does not function as a classical enzyme catalyzing a small-molecule chemical reaction. Instead, it is a structural and functional subunit of the ~1 MDa TRiC/CCT chaperonin complex, which uses ATP binding and hydrolysis to drive conformational changes that facilitate the folding of nascent and non-native polypeptides within a central enclosed chamber (smith2022mechanisticinsightsinto pages 1-3, ghozlan2022thetrickybusiness pages 1-2). The complex consists of two stacked rings, each composed of eight paralogous but distinct subunits (CCT1–CCT8 in yeast/worm nomenclature, or CCTα–θ in mammalian nomenclature) arranged in a defined order (monkemeyer2019structuralandfunctional pages 42-42, brackley2009activitiesofthe pages 1-2).
The TRiC/CCT complex is an essential molecular chaperone responsible for folding an estimated 10% of cytosolic proteins (noormohammadi2016somaticincreaseof pages 1-2, smith2022mechanisticinsightsinto pages 1-3). Its principal obligate substrates are the cytoskeletal proteins actin and tubulin, which are completely dependent on TRiC/CCT to reach their native conformations and cannot be folded by other chaperonins such as GroEL (brackley2009activitiesofthe pages 2-4, willison2018thesubstratespecificity pages 1-2, monkemeyer2019structuralandfunctional pages 31-33). Additional substrate classes include WD40 β-propeller repeat proteins and a variety of other structurally complex proteins involved in cell cycle regulation (e.g., Cdc20, Cdh1, cyclin E, Polo-like kinase 1), tumor suppression (Von Hippel-Lindau protein), and signal transduction (brackley2009activitiesofthe pages 2-4, ghozlan2022thetrickybusiness pages 6-7). The complex lowers folding energy barriers for substrates with complex topologies and can even partially encase and sequentially fold proteins larger than its central cavity (ghozlan2022thetrickybusiness pages 6-7).
Within the TRiC/CCT complex, CCT-8 has distinctive biochemical characteristics that differentiate it from other subunits:
TRiC/CCT is a cytosolic chaperonin complex (brackley2009activitiesofthe pages 1-2, zeng2024revisitingthechaperonin pages 1-4, smith2022mechanisticinsightsinto pages 1-3, smith2022mechanisticinsightsinto pages 9-10). The "C" in CCT explicitly stands for "cytosolic" (smith2022mechanisticinsightsinto pages 9-10). CCT-8, as an integral subunit of this complex, carries out its primary function in the cytoplasm/cytosol, where it assists in folding newly synthesized polypeptides emerging from ribosomes and helps maintain solubility of metastable proteins. Some evidence suggests that CCT subunits may also associate with membranes through S-palmitoylation post-translational modifications, possibly facilitating ordered assembly near the endoplasmic reticulum (ghozlan2022thetrickybusiness pages 4-5), though the predominant localization and function is cytosolic.
A landmark study by Noormohammadi et al. (2016, Nature Communications) demonstrated that cct-8 is a critical regulator of proteostasis and longevity in C. elegans. Key findings include:
CCT-8 plays a direct role in suppressing toxic protein aggregation in C. elegans models of Huntington's disease:
The TRiC/CCT complex, and cct-8 specifically, is functionally required for lifespan extension across multiple canonical C. elegans longevity paradigms:
cct-8 overexpression can extend lifespan even when the heat shock transcription factor hsf-1 is knocked down, demonstrating that the protective effects of enhanced TRiC/CCT assembly operate at least partly independently of the canonical heat shock response (noormohammadi2016somaticincreaseof pages 6-7, noormohammadi2016somaticincreaseof pages 9-10, noormohammadi2016somaticincreaseof pages 10-11). This is a significant finding because it indicates that boosting chaperonin capacity can compensate for deficient transcriptional stress responses, providing an alternative axis for maintaining proteostasis.
High levels of TRiC/CCT are essential for germline stability and the maintenance of proliferating cells in C. elegans. Adult knockdown of CCT subunits dramatically decreases germ cell numbers and destabilizes the germline (noormohammadi2016somaticincreaseof pages 6-7). This is consistent with the high demand for protein folding capacity in rapidly dividing cells.
The following table summarizes the key functional attributes of CCT-8/cct-8 in C. elegans:
| Category | Description | Evidence/Source |
|---|---|---|
| Gene Identity | cct-8 in Caenorhabditis elegans encodes T-complex protein 1 subunit theta (CCT-8/CCT8), one of the eight distinct subunits of the cytosolic TRiC/CCT chaperonin. This matches the theta subunit annotation and places the protein in the conserved TCP-1 chaperonin family. | (smith2022mechanisticinsightsinto pages 1-3, willison2018thesubstratespecificity pages 1-2, brackley2009activitiesofthe pages 1-2) |
| Protein Function | CCT-8 functions as a structural and functional subunit of the ATP-dependent TRiC/CCT folding machine, which promotes folding of obligate cytoskeletal substrates such as actin and tubulin and also assists folding/assembly of additional cytosolic proteins, including many WD40-repeat proteins. The complex facilitates folding rather than catalyzing a classic small-molecule enzymatic transformation. | (smith2022mechanisticinsightsinto pages 1-3, brackley2009activitiesofthe pages 2-4, willison2018thesubstratespecificity pages 1-2, ghozlan2022thetrickybusiness pages 6-7) |
| Subcellular Localization | TRiC/CCT is a cytosolic/cytoplasmic chaperonin complex in eukaryotic cells; therefore CCT-8’s primary site of action is the cytosol, where newly synthesized and metastable cytosolic proteins are folded. | (brackley2009activitiesofthe pages 1-2, zeng2024revisitingthechaperonin pages 1-4, smith2022mechanisticinsightsinto pages 1-3, smith2022mechanisticinsightsinto pages 9-10) |
| Biological Processes | In C. elegans, cct-8 supports proteostasis, resistance to proteotoxic stress, maintenance of protein folding capacity during aging, and suppression of toxic protein aggregation. Overexpression of cct-8 increases TRiC/CCT assembly and improves organismal protein homeostasis. | (noormohammadi2016somaticincreaseof pages 9-10, noormohammadi2016somaticincreaseof pages 6-7, noormohammadi2016somaticincreaseof pages 1-2, noormohammadi2016somaticincreaseof pages 7-8) |
| Biological Processes | cct-8 also contributes to germline stability/proliferative cell function and is linked to maintenance of tissue fitness under stress. Adult knockdown of CCT subunits decreases germ cell numbers, while high TRiC/CCT levels are important for proliferating cells and germline integrity. | (noormohammadi2016somaticincreaseof pages 6-7, noormohammadi2016somaticincreaseof pages 9-10) |
| Pathway Involvement | cct-8 is functionally required for lifespan extension in major C. elegans longevity paradigms, including reduced insulin/IGF-1 signaling (daf-2), dietary restriction (eat-2), and germline-loss signaling (glp-1). Knockdown of cct-8 shortens the extended lifespan of these long-lived backgrounds, indicating that TRiC/CCT-dependent proteostasis is a shared downstream requirement. | (noormohammadi2016somaticincreaseof pages 9-10, noormohammadi2016somaticincreaseof pages 8-9) |
| Pathway Involvement | cct-8-mediated lifespan extension is at least partly HSF-1-independent: cct-8 overexpression can remain beneficial even when hsf-1 is knocked down, suggesting that boosting TRiC/CCT assembly can bypass some dependence on the canonical heat-shock transcriptional program. | (noormohammadi2016somaticincreaseof pages 6-7, noormohammadi2016somaticincreaseof pages 9-10, noormohammadi2016somaticincreaseof pages 10-11) |
| Key Phenotypes | Somatic overexpression of cct-8 extends C. elegans lifespan by about 20% under normal conditions and by roughly 20–40% under mild heat stress/heat-stress paradigms, consistent with improved proteostasis in adulthood. | (noormohammadi2016somaticincreaseof pages 6-7, noormohammadi2016somaticincreaseof pages 7-8) |
| Key Phenotypes | cct-8 overexpression reduces polyQ67 aggregate burden, improves motility, and ameliorates proteotoxic phenotypes in worm models of Huntington-like polyglutamine toxicity without reducing total polyQ protein levels, consistent with improved folding/aggregation control rather than reduced expression. | (noormohammadi2016somaticincreaseof pages 1-2, noormohammadi2016somaticincreaseof pages 8-9, noormohammadi2016somaticincreaseof pages 7-8) |
| Key Phenotypes | Loss or downregulation of TRiC/CCT activity, including cct-8 perturbation, compromises proteostasis and promotes aggregation of disease-linked proteins; neuronal-specific CCT downregulation is sufficient to enhance neuronal polyQ67 aggregation. | (noormohammadi2016somaticincreaseof pages 6-6, calculli2021systemicregulationof pages 2-3) |
| Subunit-Specific Properties | Within TRiC/CCT, CCT-8 belongs to the low-ATPase / low-ATP-affinity CCT6 hemisphere (with CCT1/3/6/8). It retains bound ADP unusually strongly, has slow ADP off-rates, and may contribute less to ATP consumption than high-affinity subunits, implying a more specialized regulatory role in the ATPase cycle. | (ghozlan2022thetrickybusiness pages 5-6, smith2022mechanisticinsightsinto pages 3-5, ghozlan2022thetrickybusiness pages 4-5) |
| Subunit-Specific Properties | CCT-8 contributes to allosteric cooperativity and complex assembly, potentially via N-terminal features that function partly independently of ATP hydrolysis. These properties suggest that cct-8 is not merely interchangeable with other subunits but helps define TRiC/CCT architecture and regulation. | (ghozlan2022thetrickybusiness pages 5-6) |
| Subunit-Specific Properties | CCT-8 also participates directly in substrate binding contacts. Structural studies indicate many substrates contact CCT8, and actin and tubulin each make contacts with CCT8-containing apical domains during the folding cycle, helping position/stabilize folding intermediates. | (smith2022mechanisticinsightsinto pages 3-5, smith2022mechanisticinsightsinto pages 5-8) |
| Structural Context | The eight TRiC/CCT subunits occupy fixed positions within each ring; proposed arrangements place CCT8 at a defined site and indicate it may participate in homotypic inter-ring contacts, supporting its contribution to complex architecture as well as folding function. | (monkemeyer2019structuralandfunctional pages 42-42, monkemeyer2019structuralandfunctional pages 29-31, brackley2009activitiesofthe pages 2-4) |
Table: This table summarizes the verified functional annotation of C. elegans cct-8/CCT-8 as the theta subunit of the TRiC/CCT chaperonin. It highlights molecular function, localization, pathway links, phenotypes, and subunit-specific properties most relevant to proteostasis, aging, and polyQ aggregation.
The functional importance of CCT8 is broadly conserved across eukaryotes. In mammals, CCT8 has been identified as upregulated in several cancers (hepatocellular carcinoma, colorectal cancer) and is associated with tumor progression (OpenTargets Search: -CCT8). The human ortholog has been shown to be essential for T cell maturation, selection, and function, with loss of CCT8 in T cells impairing proteostasis, nuclear actin filament formation, and immune responses. Recent work has also identified FKBP4 (an Hsp90 co-chaperone) as a facilitator of CCT8 folding, connecting the Hsp90 system to TRiC/CCT-dependent proteostasis. In Arabidopsis, CCT8 overexpression similarly ameliorates protein aggregation in differentiated cells and confers stress tolerance (zeng2024revisitingthechaperonin pages 6-8).
cct-8 in C. elegans encodes the theta subunit of the TRiC/CCT cytosolic chaperonin complex, an essential ATP-dependent molecular machine that folds actin, tubulin, WD40 proteins, and approximately 10% of the cytosolic proteome. Within the complex, CCT-8 occupies a defined position in the low-ATPase hemisphere and plays a specialized role in substrate binding, allosteric regulation, and complex assembly rather than direct ATP consumption. In C. elegans, cct-8 is a critical determinant of proteostasis during aging: its overexpression extends lifespan, suppresses polyglutamine aggregation, and improves stress resistance, while its loss-of-function compromises the longevity conferred by reduced insulin signaling, dietary restriction, and germline ablation pathways. The protein functions primarily in the cytosol and is essential for both somatic tissue maintenance during aging and germline cell integrity.
References
(smith2022mechanisticinsightsinto pages 1-3): Theresa M. Smith and Barry M. Willardson. Mechanistic insights into protein folding by the eukaryotic chaperonin complex cct. Biochemical Society Transactions, 50:1403-1414, Oct 2022. URL: https://doi.org/10.1042/bst20220591, doi:10.1042/bst20220591. This article has 23 citations and is from a peer-reviewed journal.
(willison2018thesubstratespecificity pages 1-2): Keith R. Willison. The substrate specificity of eukaryotic cytosolic chaperonin cct. Philosophical Transactions of the Royal Society B: Biological Sciences, 373:20170192, Jun 2018. URL: https://doi.org/10.1098/rstb.2017.0192, doi:10.1098/rstb.2017.0192. This article has 76 citations and is from a domain leading peer-reviewed journal.
(brackley2009activitiesofthe pages 1-2): Karen I. Brackley and Julie Grantham. Activities of the chaperonin containing tcp-1 (cct): implications for cell cycle progression and cytoskeletal organisation. Cell Stress and Chaperones, 14:23-31, Jan 2009. URL: https://doi.org/10.1007/s12192-008-0057-x, doi:10.1007/s12192-008-0057-x. This article has 215 citations and is from a peer-reviewed journal.
(ghozlan2022thetrickybusiness pages 1-2): Heba Ghozlan, Amanda Cox, Daniel Nierenberg, Stephen King, and Annette R. Khaled. The tricky business of protein folding in health and disease. Frontiers in Cell and Developmental Biology, May 2022. URL: https://doi.org/10.3389/fcell.2022.906530, doi:10.3389/fcell.2022.906530. This article has 35 citations.
(monkemeyer2019structuralandfunctional pages 42-42): Leonie Mönkemeyer. Structural and functional studies on the eukaryotic chaperonin tric/cct and its cooperating chaperone hgh1. Dissertation, Jan 2019. URL: https://doi.org/10.5282/edoc.23750, doi:10.5282/edoc.23750. This article has 0 citations.
(noormohammadi2016somaticincreaseof pages 1-2): Alireza Noormohammadi, Amirabbas Khodakarami, Ricardo Gutierrez-Garcia, Hyun Ju Lee, Seda Koyuncu, Tim König, Christina Schindler, Isabel Saez, Azra Fatima, Christoph Dieterich, and David Vilchez. Somatic increase of cct8 mimics proteostasis of human pluripotent stem cells and extends c. elegans lifespan. Nature Communications, Nov 2016. URL: https://doi.org/10.1038/ncomms13649, doi:10.1038/ncomms13649. This article has 96 citations and is from a highest quality peer-reviewed journal.
(brackley2009activitiesofthe pages 2-4): Karen I. Brackley and Julie Grantham. Activities of the chaperonin containing tcp-1 (cct): implications for cell cycle progression and cytoskeletal organisation. Cell Stress and Chaperones, 14:23-31, Jan 2009. URL: https://doi.org/10.1007/s12192-008-0057-x, doi:10.1007/s12192-008-0057-x. This article has 215 citations and is from a peer-reviewed journal.
(monkemeyer2019structuralandfunctional pages 31-33): Leonie Mönkemeyer. Structural and functional studies on the eukaryotic chaperonin tric/cct and its cooperating chaperone hgh1. Dissertation, Jan 2019. URL: https://doi.org/10.5282/edoc.23750, doi:10.5282/edoc.23750. This article has 0 citations.
(ghozlan2022thetrickybusiness pages 6-7): Heba Ghozlan, Amanda Cox, Daniel Nierenberg, Stephen King, and Annette R. Khaled. The tricky business of protein folding in health and disease. Frontiers in Cell and Developmental Biology, May 2022. URL: https://doi.org/10.3389/fcell.2022.906530, doi:10.3389/fcell.2022.906530. This article has 35 citations.
(ghozlan2022thetrickybusiness pages 5-6): Heba Ghozlan, Amanda Cox, Daniel Nierenberg, Stephen King, and Annette R. Khaled. The tricky business of protein folding in health and disease. Frontiers in Cell and Developmental Biology, May 2022. URL: https://doi.org/10.3389/fcell.2022.906530, doi:10.3389/fcell.2022.906530. This article has 35 citations.
(smith2022mechanisticinsightsinto pages 3-5): Theresa M. Smith and Barry M. Willardson. Mechanistic insights into protein folding by the eukaryotic chaperonin complex cct. Biochemical Society Transactions, 50:1403-1414, Oct 2022. URL: https://doi.org/10.1042/bst20220591, doi:10.1042/bst20220591. This article has 23 citations and is from a peer-reviewed journal.
(smith2022mechanisticinsightsinto pages 5-8): Theresa M. Smith and Barry M. Willardson. Mechanistic insights into protein folding by the eukaryotic chaperonin complex cct. Biochemical Society Transactions, 50:1403-1414, Oct 2022. URL: https://doi.org/10.1042/bst20220591, doi:10.1042/bst20220591. This article has 23 citations and is from a peer-reviewed journal.
(ghozlan2022thetrickybusiness pages 4-5): Heba Ghozlan, Amanda Cox, Daniel Nierenberg, Stephen King, and Annette R. Khaled. The tricky business of protein folding in health and disease. Frontiers in Cell and Developmental Biology, May 2022. URL: https://doi.org/10.3389/fcell.2022.906530, doi:10.3389/fcell.2022.906530. This article has 35 citations.
(zeng2024revisitingthechaperonin pages 1-4): Chenglong Zeng, Shenqi Han, Yonglong Pan, Zhao Huang, Binhao Zhang, and Bixiang Zhang. Revisiting the chaperonin t‐complex protein‐1 ring complex in human health and disease: a proteostasis modulator and beyond. Clinical and Translational Medicine, Feb 2024. URL: https://doi.org/10.1002/ctm2.1592, doi:10.1002/ctm2.1592. This article has 24 citations and is from a peer-reviewed journal.
(smith2022mechanisticinsightsinto pages 9-10): Theresa M. Smith and Barry M. Willardson. Mechanistic insights into protein folding by the eukaryotic chaperonin complex cct. Biochemical Society Transactions, 50:1403-1414, Oct 2022. URL: https://doi.org/10.1042/bst20220591, doi:10.1042/bst20220591. This article has 23 citations and is from a peer-reviewed journal.
(noormohammadi2016somaticincreaseof pages 7-8): Alireza Noormohammadi, Amirabbas Khodakarami, Ricardo Gutierrez-Garcia, Hyun Ju Lee, Seda Koyuncu, Tim König, Christina Schindler, Isabel Saez, Azra Fatima, Christoph Dieterich, and David Vilchez. Somatic increase of cct8 mimics proteostasis of human pluripotent stem cells and extends c. elegans lifespan. Nature Communications, Nov 2016. URL: https://doi.org/10.1038/ncomms13649, doi:10.1038/ncomms13649. This article has 96 citations and is from a highest quality peer-reviewed journal.
(noormohammadi2016somaticincreaseof pages 6-7): Alireza Noormohammadi, Amirabbas Khodakarami, Ricardo Gutierrez-Garcia, Hyun Ju Lee, Seda Koyuncu, Tim König, Christina Schindler, Isabel Saez, Azra Fatima, Christoph Dieterich, and David Vilchez. Somatic increase of cct8 mimics proteostasis of human pluripotent stem cells and extends c. elegans lifespan. Nature Communications, Nov 2016. URL: https://doi.org/10.1038/ncomms13649, doi:10.1038/ncomms13649. This article has 96 citations and is from a highest quality peer-reviewed journal.
(noormohammadi2016somaticincreaseof pages 8-9): Alireza Noormohammadi, Amirabbas Khodakarami, Ricardo Gutierrez-Garcia, Hyun Ju Lee, Seda Koyuncu, Tim König, Christina Schindler, Isabel Saez, Azra Fatima, Christoph Dieterich, and David Vilchez. Somatic increase of cct8 mimics proteostasis of human pluripotent stem cells and extends c. elegans lifespan. Nature Communications, Nov 2016. URL: https://doi.org/10.1038/ncomms13649, doi:10.1038/ncomms13649. This article has 96 citations and is from a highest quality peer-reviewed journal.
(calculli2021systemicregulationof pages 2-3): Giuseppe Calculli, Hyun Ju Lee, Koning Shen, Uyen Pham, Marija Herholz, Aleksandra Trifunovic, Andrew Dillin, and David Vilchez. Systemic regulation of mitochondria by germline proteostasis prevents protein aggregation in the soma of c. elegans. Jun 2021. URL: https://doi.org/10.1126/sciadv.abg3012, doi:10.1126/sciadv.abg3012. This article has 65 citations and is from a highest quality peer-reviewed journal.
(noormohammadi2016somaticincreaseof pages 6-6): Alireza Noormohammadi, Amirabbas Khodakarami, Ricardo Gutierrez-Garcia, Hyun Ju Lee, Seda Koyuncu, Tim König, Christina Schindler, Isabel Saez, Azra Fatima, Christoph Dieterich, and David Vilchez. Somatic increase of cct8 mimics proteostasis of human pluripotent stem cells and extends c. elegans lifespan. Nature Communications, Nov 2016. URL: https://doi.org/10.1038/ncomms13649, doi:10.1038/ncomms13649. This article has 96 citations and is from a highest quality peer-reviewed journal.
(noormohammadi2016somaticincreaseof pages 9-10): Alireza Noormohammadi, Amirabbas Khodakarami, Ricardo Gutierrez-Garcia, Hyun Ju Lee, Seda Koyuncu, Tim König, Christina Schindler, Isabel Saez, Azra Fatima, Christoph Dieterich, and David Vilchez. Somatic increase of cct8 mimics proteostasis of human pluripotent stem cells and extends c. elegans lifespan. Nature Communications, Nov 2016. URL: https://doi.org/10.1038/ncomms13649, doi:10.1038/ncomms13649. This article has 96 citations and is from a highest quality peer-reviewed journal.
(noormohammadi2016somaticincreaseof pages 10-11): Alireza Noormohammadi, Amirabbas Khodakarami, Ricardo Gutierrez-Garcia, Hyun Ju Lee, Seda Koyuncu, Tim König, Christina Schindler, Isabel Saez, Azra Fatima, Christoph Dieterich, and David Vilchez. Somatic increase of cct8 mimics proteostasis of human pluripotent stem cells and extends c. elegans lifespan. Nature Communications, Nov 2016. URL: https://doi.org/10.1038/ncomms13649, doi:10.1038/ncomms13649. This article has 96 citations and is from a highest quality peer-reviewed journal.
(monkemeyer2019structuralandfunctional pages 29-31): Leonie Mönkemeyer. Structural and functional studies on the eukaryotic chaperonin tric/cct and its cooperating chaperone hgh1. Dissertation, Jan 2019. URL: https://doi.org/10.5282/edoc.23750, doi:10.5282/edoc.23750. This article has 0 citations.
(OpenTargets Search: -CCT8): Open Targets Query (-CCT8, 7 results). Buniello, A. et al. (2025). Open Targets Platform: facilitating therapeutic hypotheses building in drug discovery. Nucleic Acids Research.
(zeng2024revisitingthechaperonin pages 6-8): Chenglong Zeng, Shenqi Han, Yonglong Pan, Zhao Huang, Binhao Zhang, and Bixiang Zhang. Revisiting the chaperonin t‐complex protein‐1 ring complex in human health and disease: a proteostasis modulator and beyond. Clinical and Translational Medicine, Feb 2024. URL: https://doi.org/10.1002/ctm2.1592, doi:10.1002/ctm2.1592. This article has 24 citations and is from a peer-reviewed journal.
Gene: cct-8 / ORF Y55F3AR.3 / WormBase WBGene00021934
UniProt: Q9N358 (TCPQ_CAEEL), "T-complex protein 1 subunit theta" (CCT-theta / TCP-1-theta), 548 aa.
NCBI taxon: 6239.
This is a research journal. Provenance is recorded inline as [PMID:xxxx "verbatim quote"]
or [file:... "quote"]. KNOWN vs NOT-KNOWN are separated at the end.
cct-8 encodes the theta (θ) subunit of the eukaryotic cytosolic chaperonin CCT
(chaperonin-containing TCP-1), also called TRiC (TCP-1 ring complex). UniProt:
"Belongs to the TCP-1 chaperonin family." InterPro domains identify it specifically as the
theta paralog: IPR012721 Chap_CCT_theta, plus the pan-family IPR017998 Chaperone_TCP-1,
IPR002194 Chaperonin_TCP-1_CS, and the Cpn60/GroEL/TCP-1 fold (IPR002423). PANTHER family
PTHR11353 (CHAPERONIN). NCBIfam TIGR02346 chap_CCT_theta and CDD cd03341 TCP1_theta are
theta-subunit-specific, so the subunit assignment is unambiguous.
CCT/TRiC is a ~1 MDa double-ring machine; each ring is a hetero-octamer of eight distinct but
paralogous subunits (CCT1–CCT8 / alpha–theta), arranged in a fixed order. In C. elegans the
eight paralogs are cct-1..cct-8. The assembled complex, not any single subunit, is the folding
machine. PMID:15704212
CCT/TRiC is an ATP-dependent foldase. Each subunit is a member of the group II chaperonin
(GroEL/Cpn60-like) fold with an equatorial ATP-binding/hydrolysis domain, an intermediate
domain, and a substrate-binding apical domain. ATP binding and hydrolysis by the subunits drives
the folding cycle. PMID:16762366
The complex acts as a genuine catalyst of folding. PMID:16762366
The eight subunits are functionally non-equivalent — they have distinct substrate contacts and
distinct roles despite the shared fold. PMID:15704212 The conserved equatorial ATP-binding motif is required for the subunit-specific
activities. PMID:15704212
The GOA molecular-function annotations (ATP binding GO:0005524, ATP hydrolysis GO:0016887,
ATP-dependent protein folding chaperone GO:0140662) are all consistent with this conserved
mechanism and with the InterPro/PANTHER family assignment.
UniProt curates a worm-specific in-vivo role from a genome-wide RNAi screen: cct-8 is required
for correct localization of the germ-granule (P-granule) protein PGL-1.
[file:worm/cct-8/cct-8-uniprot.txt "Required for correct subcellular localization of pgl-1."]
Disruption phenotype: [file:worm/cct-8/cct-8-uniprot.txt "Low and diffuse subcellular
localization of pgl-1 in embryos rather than confined to granules in somatic cells."] The source
is the Updike & Strome genome-wide RNAi screen for P-granule genes; cct-8 was among 173 hits.
PMID:19805813 NOTE: the cached
PMID:19805813 record is abstract-only (full_text_available: false); the abstract does not name
cct-8 or pgl-1, so the specific pgl-1 phenotype is taken from the UniProt curation (which read
the full text), not quoted from the abstract.
The pgl-1 phenotype is most parsimoniously explained by cct-8's canonical chaperonin role: PGL-1
condensation into P granules likely depends on CCT/TRiC-assisted folding of PGL-1 itself or of a
partner. Whether PGL-1 (or actin, which scaffolds germ granules) is the direct CCT substrate has
not been established.
Protein-level evidence: the mature protein was directly sequenced by Edman/MS (UniProt
"Direct protein sequencing" keyword; PE:1 evidence at protein level), confirming expression.
Subcellular location: cytoplasm (UniProt SUBCELLULAR LOCATION "Cytoplasm"; by similarity to
human CCT-theta P50990). Consistent with the cytosolic role of CCT/TRiC. GOA has GO:0005737
cytoplasm (IEA). The more precise term would be cytosol (GO:0005829), but cytoplasm is not wrong.
There is no unfolded protein binding (GO:0051082) annotation in the C. elegans GOA (unlike the
yeast/human orthologs), so no MODIFY is needed for that term here.
Deep research (cct-8-deep-research-falcon.md, Edison, 32 citations) surfaced two key
C. elegans functional papers and subunit-level structural detail:
Noormohammadi et al. 2016, Nat Commun PMID:27892468: cct-8/CCT8 is rate-limiting for
TRiC/CCT assembly and its somatic increase boosts proteostasis and longevity.
PMID:27892468; PMID:27892468; PMID:27892468; PMID:27892468. cct-8 is required for lifespan extension in daf-2, eat-2, and glp-1
long-lived backgrounds (from the paper's body / deep-research synthesis), and its protective
effect can be partly HSF-1-independent.
Calculli et al. 2021, Sci Adv PMID:34172445: cct-8 acts cell-autonomously in neurons to
prevent polyglutamine aggregation. PMID:34172445.
Subunit-specific properties (from CCT/TRiC structural reviews via deep research): the theta
subunit is a LOW-ATPase subunit (the "CCT6 hemisphere": CCT1/3/6/8), retains bound ADP, and
contributes to substrate binding, allostery, and complex assembly rather than bulk ATP
consumption. [file:worm/cct-8/cct-8-deep-research-falcon.md "CCT-8 occupies a defined position
in the low-ATPase hemisphere and plays a specialized role in substrate binding, allosteric
regulation, and complex assembly"]; [file:worm/cct-8/cct-8-deep-research-falcon.md "Both actin
and tubulin make specific contacts with CCT-8-containing apical domains during folding"].
Impact on the review:
- Core-function molecular_function set to GO:0005524 (ATP binding) rather than ATP hydrolysis,
because theta is a low-ATPase subunit; contributes_to_molecular_function = GO:0140662.
- GO:0016887 (ATP hydrolysis) existing annotation kept as ACCEPT (family-level InterPro; theta
retains the catalytic P-loop/aspartate) with the low-ATPase nuance recorded.
- Knowledge gap #1 reframed: theta substrate contacts ARE structurally characterized, so the gap
is now primarily the ONTOLOGY gap (no MF term for a chaperonin substrate-binding subunit) plus
the residual BIOLOGY gap of the native worm client set.
id: Q9N358
gene_symbol: cct-8
product_type: PROTEIN
status: COMPLETE
taxon:
id: NCBITaxon:6239
label: Caenorhabditis elegans
description: >-
cct-8 encodes the theta (CCT-theta / TCP-1-theta) subunit of the eukaryotic
cytosolic chaperonin CCT (chaperonin-containing TCP-1), also known as TRiC.
CCT/TRiC is an ATP-dependent, hetero-oligomeric double-ring chaperonin whose
two rings are each built from eight distinct but paralogous subunits
(CCT1-CCT8 / alpha-theta); cct-8 is the theta paralog. The assembled complex,
not any individual subunit, is the folding machine: it uses cycles of ATP
binding and hydrolysis by its subunits to fold roughly a tenth of the cytosolic
proteome, most notably the obligate cytoskeletal substrates actin and tubulin,
as well as WD40 beta-propeller proteins. The theta subunit contributes an
equatorial nucleotide-binding module and an apical substrate-binding surface;
it is one of the low-ATPase subunits and participates in substrate contacts and
in allosteric coordination of the folding cycle. In C. elegans, cct-8 acts in
the cytoplasm, is required for correct subcellular localization of the
germ-granule protein PGL-1, and is a limiting determinant of TRiC/CCT assembly:
raising CCT8 levels increases assembled chaperonin, suppresses aggregation of
polyglutamine and mutant Huntingtin proteins, and extends lifespan, so cct-8
supports cytosolic protein homeostasis during aging and in the germline.
existing_annotations:
- term:
id: GO:0006457
label: protein folding
evidence_type: IBA
original_reference_id: GO_REF:0000033
qualifier: involved_in
review:
summary: >-
cct-8 is the theta subunit of the cytosolic chaperonin CCT/TRiC, which
catalyzes ATP-dependent folding of cytoskeletal and other cytosolic
substrates. Protein folding is the core biological process for this
subunit.
action: ACCEPT
reason: >-
The phylogenetic (IBA) inference is fully consistent with the conserved
chaperonin family assignment (PANTHER PTHR11353; InterPro theta-subunit
signatures) and with direct biochemical demonstration that purified CCT
catalyzes actin folding. In C. elegans, raising CCT8 levels increases
assembled TRiC/CCT and suppresses protein aggregation, confirming the
folding role in vivo.
supported_by:
- reference_id: PMID:16762366
supporting_text: >-
The eukaryotic cytosolic chaperonin CCT is an essential ATP-dependent
protein folding machine whose action is required for folding the
cytoskeletal proteins actin and tubulin
- reference_id: PMID:27892468
supporting_text: >-
increased TRiC/CCT complex is required to avoid aggregation of mutant
Huntingtin protein
- reference_id: file:interpro/panther/PTHR11353/PTHR11353-metadata.yaml
supporting_text: CHAPERONIN
- term:
id: GO:0005832
label: chaperonin-containing T-complex
evidence_type: IBA
original_reference_id: GO_REF:0000033
qualifier: part_of
review:
summary: >-
cct-8 is an integral subunit of the chaperonin-containing T-complex
(CCT/TRiC), which is built from eight paralogous subunits per ring.
action: ACCEPT
reason: >-
The CCT complex is assembled from a stoichiometric array of subunits
Cct1p-Cct8p; cct-8 is the theta subunit. In C. elegans, ectopic CCT8 is
rate-limiting for assembly of the complex. Complex membership is the most
important and best-supported annotation for this gene.
supported_by:
- reference_id: PMID:15704212
supporting_text: >-
Eukaryotic chaperonins, the Cct complexes, are assembled into two
rings, each of which is composed of a stoichiometric array of eight
different subunits, which are denoted Cct1p-Cct8p.
- reference_id: PMID:27892468
supporting_text: >-
ectopic expression of a single subunit (CCT8) is sufficient to
increase TRiC/CCT assembly
- term:
id: GO:0005524
label: ATP binding
evidence_type: IEA
original_reference_id: GO_REF:0000002
qualifier: enables
review:
summary: >-
Each CCT subunit binds ATP/ADP through the conserved equatorial
nucleotide-binding site of the group II chaperonin fold; nucleotide
binding is integral to the folding cycle.
action: ACCEPT
reason: >-
ATP binding is a conserved, well-established property of CCT/TRiC
subunits, consistent with the InterPro chaperonin domains and the
ATP-dependent mechanism of the complex. The theta subunit is a
low-ATPase subunit that binds and retains nucleotide, so ATP binding is
the most accurate concrete molecular-function annotation for it.
supported_by:
- reference_id: PMID:16762366
supporting_text: >-
The eukaryotic cytosolic chaperonin CCT is an essential ATP-dependent
protein folding machine
- term:
id: GO:0005737
label: cytoplasm
evidence_type: IEA
original_reference_id: GO_REF:0000120
qualifier: located_in
review:
summary: >-
CCT/TRiC is a cytosolic chaperonin; cct-8 acts in the cytoplasm on
cytosolic substrates.
action: ACCEPT
reason: >-
Cytoplasmic localization is consistent with the known biology of the
cytosolic chaperonin and with the UniProt subcellular location. The more
specific term cytosol (GO:0005829) would be preferable, but the broader
cytoplasm annotation is not incorrect and is retained.
supported_by:
- reference_id: PMID:16762366
supporting_text: The eukaryotic cytosolic chaperonin CCT
- term:
id: GO:0006457
label: protein folding
evidence_type: IEA
original_reference_id: GO_REF:0000002
qualifier: involved_in
review:
summary: >-
InterPro domain-based annotation of protein folding, duplicating the IBA
protein-folding annotation.
action: ACCEPT
reason: >-
Consistent electronic (InterPro) support for the core protein-folding
process, in agreement with the IBA annotation and the conserved
chaperonin mechanism.
supported_by:
- reference_id: PMID:16762366
supporting_text: >-
Yeast CCT catalyses the folding of yeast ACT1p and human beta-actin
with nearly identical rate constants and yields.
- term:
id: GO:0016887
label: ATP hydrolysis activity
evidence_type: IEA
original_reference_id: GO_REF:0000002
qualifier: enables
review:
summary: >-
The CCT subunits form ATPases; ATP hydrolysis around the ring powers the
substrate-folding cycle of the chaperonin.
action: ACCEPT
reason: >-
ATP hydrolysis is a conserved catalytic activity of the CCT/TRiC family,
supported by the InterPro chaperonin domains. This is a family-level
electronic annotation; the theta subunit specifically is one of the
low-ATPase subunits that retains bound ADP, but it preserves the
catalytic P-loop and aspartate, so the term is retained rather than
removed.
supported_by:
- reference_id: PMID:16762366
supporting_text: >-
The eukaryotic cytosolic chaperonin CCT is an essential ATP-dependent
protein folding machine
- reference_id: file:worm/cct-8/cct-8-deep-research-falcon.md
supporting_text: >-
CCT-8 occupies a defined position in the low-ATPase hemisphere and
plays a specialized role in substrate binding, allosteric regulation,
and complex assembly
- term:
id: GO:0140662
label: ATP-dependent protein folding chaperone
evidence_type: IEA
original_reference_id: GO_REF:0000002
qualifier: enables
review:
summary: >-
ATP-dependent protein folding chaperone is the most informative
molecular-function term for CCT/TRiC; cct-8 contributes to this activity
as a subunit of the complex.
action: ACCEPT
reason: >-
This term precisely captures the activity of the CCT chaperonin. Strictly
it is a complex-level activity to which the theta subunit contributes
rather than one it enables alone, but the annotation is appropriate and
is the best available molecular-function descriptor for this gene.
supported_by:
- reference_id: PMID:16762366
supporting_text: >-
The eukaryotic cytosolic chaperonin CCT is an essential ATP-dependent
protein folding machine
core_functions:
- description: >-
cct-8 is the theta subunit of the cytosolic chaperonin CCT/TRiC. As part of
the hetero-oligomeric complex it binds nucleotide through its equatorial
domain and presents an apical substrate-binding surface, contributing to the
ATP-dependent folding of actin, tubulin, and other cytosolic clients. The
foldase activity is a property of the assembled complex, to which the theta
subunit contributes; theta is a low-ATPase subunit whose distinctive
contribution is substrate binding and allosteric coordination rather than
bulk ATP consumption.
molecular_function:
id: GO:0005524
label: ATP binding
contributes_to_molecular_function:
id: GO:0140662
label: ATP-dependent protein folding chaperone
directly_involved_in:
- id: GO:0006457
label: protein folding
locations:
- id: GO:0005737
label: cytoplasm
in_complex:
id: GO:0005832
label: chaperonin-containing T-complex
supported_by:
- reference_id: PMID:16762366
supporting_text: >-
The eukaryotic cytosolic chaperonin CCT is an essential ATP-dependent
protein folding machine whose action is required for folding the
cytoskeletal proteins actin and tubulin
- reference_id: PMID:15704212
supporting_text: >-
Eukaryotic chaperonins, the Cct complexes, are assembled into two
rings, each of which is composed of a stoichiometric array of eight
different subunits, which are denoted Cct1p-Cct8p.
- reference_id: PMID:27892468
supporting_text: >-
ectopic expression of a single subunit (CCT8) is sufficient to increase
TRiC/CCT assembly
knowledge_gaps:
- gap_statement: >-
The native C. elegans client repertoire that specifically depends on the
theta (CCT8) subunit is undefined, and there is no GO molecular-function
term that expresses "substrate-binding subunit of the CCT chaperonin". The
theta subunit's own activity can therefore only be annotated as the
complex-level foldase (GO:0140662) or as generic ATP binding/hydrolysis,
leaving cct-8 molecular-function-dark at the subunit level.
boundary: >-
It is firmly established that cct-8 is the theta subunit of the
eight-membered CCT/TRiC ring, that the assembled complex folds actin,
tubulin, WD40 proteins, and about 10% of the cytosolic proteome, and that
the eight subunits are functionally non-equivalent. Structural work in
CCT/TRiC further shows theta is a low-ATPase subunit that makes substrate
contacts (actin and tubulin contact CCT8-containing apical domains) and
contributes to allostery and assembly.
gap_kind:
- ONTOLOGY
- BIOLOGY
dark_aspect: MF_DARK
status: OPEN
significance: >-
CCT subunits are individually essential and non-redundant, so
subunit-specific substrate engagement underlies the complex's client
selectivity. Because no ontology term names a chaperonin substrate-binding
subunit activity, the theta subunit's characterized structural/regulatory
role cannot be curated, and its native worm-specific clients remain
unmapped.
resolution: >-
Affinity-proteomics of the C. elegans CCT/TRiC to define native theta
clients, plus crosslinking or cryo-EM mapping of theta apical-domain
contacts, would define the subunit contribution; a new GO
molecular-function term for a chaperonin substrate-binding subunit activity
would let the knowledge be expressed.
provenance:
- reference_id: PMID:15704212
supporting_text: >-
These results provide evidence for functional differences among Cct
subunits and for physiological properties of unassembled subunits.
- reference_id: file:worm/cct-8/cct-8-deep-research-falcon.md
supporting_text: >-
Both actin and tubulin make specific contacts with CCT-8-containing
apical domains during folding
proposed_terms:
- proposed_name: chaperonin substrate-binding subunit activity
proposed_definition: >-
A molecular function of a single subunit of a group II chaperonin
(CCT/TRiC) that presents an apical-domain substrate-binding surface and
contributes subunit-specific contacts to the ATP-dependent folding of
client proteins by the assembled chaperonin, without itself folding a
substrate independently of the complex.
justification: >-
Individual CCT subunits such as cct-8/theta have no adequate GO
molecular-function term: they can currently be annotated only with the
complex-level foldase activity (GO:0140662) or a generic catalytic term,
neither of which captures the subunit-specific substrate-binding
contribution that distinguishes the eight paralogous subunits.
proposed_parent:
id: GO:0003674
label: molecular_function
- gap_statement: >-
It is unknown whether the germ-granule protein PGL-1 is a direct CCT/TRiC
client of cct-8 or whether the pgl-1 mislocalization seen on cct-8 depletion
is an indirect consequence of impaired folding of another substrate (for
example actin, which scaffolds germ granules).
boundary: >-
cct-8 depletion causes low, diffuse PGL-1 localization in C. elegans embryos
rather than confinement to granules, and cct-8 knockdown promotes neuronal
polyglutamine aggregation, identifying cct-8 as required for correct protein
solubility/localization in vivo. Whether PGL-1 physically engages the
chaperonin has not been tested.
gap_kind:
- BIOLOGY
dark_aspect: RESIDUAL_SUBGAP
status: OPEN
significance: >-
Distinguishing a direct chaperonin-client relationship from an indirect
cytoskeletal effect would clarify how the general folding machinery supports
germline biomolecular-condensate (P-granule) assembly.
resolution: >-
Test whether PGL-1 physically engages CCT/TRiC (co-purification, in vitro
folding assays) and whether actin/tubulin folding defects alone reproduce
the P-granule phenotype.
provenance:
- reference_id: file:worm/cct-8/cct-8-uniprot.txt
supporting_text: Low and diffuse subcellular localization of pgl-1
- reference_id: PMID:34172445
supporting_text: knockdown of cct-8 promotes neuronal polyQ67 aggregation
proposed_new_terms:
- proposed_name: chaperonin substrate-binding subunit activity
proposed_definition: >-
A molecular function of a single subunit of a group II chaperonin (CCT/TRiC)
that presents an apical-domain substrate-binding surface and contributes
subunit-specific contacts to the ATP-dependent folding of client proteins by
the assembled chaperonin, without itself folding a substrate independently of
the complex.
justification: >-
Individual CCT subunits have no adequate GO molecular-function term and can
only be annotated with the complex-level foldase activity or a generic
catalytic term, obscuring subunit-specific substrate selectivity.
proposed_parent:
id: GO:0003674
label: molecular_function
suggested_questions:
- question: >-
Which native C. elegans clients depend specifically on the theta (cct-8)
subunit contacts, as opposed to the CCT/TRiC complex as a whole?
- question: >-
Is PGL-1 a direct CCT/TRiC substrate, or is its P-granule mislocalization on
cct-8 depletion an indirect consequence of impaired actin/tubulin folding?
- question: >-
Is the low-ATPase, substrate-binding character of the theta subunit seen in
mammalian/yeast CCT structures conserved and functionally important in
C. elegans?
suggested_experiments:
- description: >-
Perform affinity purification/mass spectrometry of tagged cct-8 (or the
assembled CCT/TRiC) from C. elegans to identify native clients, and test
whether PGL-1 co-purifies with the chaperonin.
hypothesis: >-
cct-8 engages a defined set of native C. elegans clients that includes
cytoskeletal proteins and may include germ-granule components.
- description: >-
Map theta-subunit apical-domain substrate contacts by crosslinking mass
spectrometry or cryo-EM of CCT/TRiC caught with folding substrates, to define
the subunit-specific substrate-binding contribution.
hypothesis: >-
The theta apical domain makes distinct substrate contacts that differ from
the other seven CCT subunits.
references:
- id: GO_REF:0000002
title: Gene Ontology annotation through association of InterPro records with GO terms
findings: []
- id: GO_REF:0000033
title: Annotation inferences using phylogenetic trees
findings: []
- id: GO_REF:0000120
title: Combined Automated Annotation using Multiple IEA Methods
findings: []
- id: PMID:16762366
title: Quantitative actin folding reactions using yeast CCT purified via an internal tag in the CCT3/gamma subunit.
findings:
- statement: CCT/TRiC is an ATP-dependent folding machine for actin and tubulin.
supporting_text: >-
The eukaryotic cytosolic chaperonin CCT is an essential ATP-dependent
protein folding machine whose action is required for folding the
cytoskeletal proteins actin and tubulin
- statement: Purified yeast CCT catalyzes actin folding.
supporting_text: >-
Yeast CCT catalyses the folding of yeast ACT1p and human beta-actin with
nearly identical rate constants and yields.
reference_review:
relevance: HIGH
correctness: VERIFIED
review_notes: >-
PubMed-verified. A yeast-based study, but it establishes the conserved
ATP-dependent foldase mechanism and actin/tubulin/WD40 substrate scope of
CCT/TRiC that applies to the C. elegans theta subunit. Used for mechanism,
not for a worm-specific claim.
- id: PMID:15704212
title: Physiological effects of unassembled chaperonin Cct subunits in the yeast Saccharomyces cerevisiae.
findings:
- statement: CCT is built from eight distinct subunits Cct1p-Cct8p per ring.
supporting_text: >-
Eukaryotic chaperonins, the Cct complexes, are assembled into two rings,
each of which is composed of a stoichiometric array of eight different
subunits, which are denoted Cct1p-Cct8p.
- statement: The CCT subunits are functionally non-equivalent.
supporting_text: >-
These results provide evidence for functional differences among Cct
subunits and for physiological properties of unassembled subunits.
reference_review:
relevance: MEDIUM
correctness: VERIFIED
review_notes: >-
PubMed-verified. Yeast study establishing the eight-subunit composition of
CCT and functional differences among subunits, directly relevant to the
theta-subunit knowledge gap. Not a worm-specific source.
- id: PMID:27892468
title: Somatic increase of CCT8 mimics proteostasis of human pluripotent stem cells and extends C. elegans lifespan.
findings:
- statement: >-
A single CCT8 subunit is rate-limiting for TRiC/CCT assembly, and
increased complex prevents mutant Huntingtin aggregation.
supporting_text: >-
ectopic expression of a single subunit (CCT8) is sufficient to increase
TRiC/CCT assembly
- statement: Somatic CCT8 increase extends C. elegans lifespan TRiC/CCT-dependently.
supporting_text: >-
increased expression of CCT8 in somatic tissues extends Caenorhabditis
elegans lifespan in a TRiC/CCT-dependent manner
- statement: CCT8 increase corrects age-associated proteostasis decline in worm HD models.
supporting_text: >-
ameliorates the age-associated demise of proteostasis and corrects
proteostatic deficiencies in worm models
reference_review:
relevance: HIGH
correctness: VERIFIED
review_notes: >-
PubMed-verified C. elegans primary paper (full text available). Direct
worm experimental evidence that cct-8/CCT8 is rate-limiting for TRiC/CCT
assembly and that raising it suppresses aggregation and extends lifespan.
Establishes the in-vivo proteostasis role of cct-8.
- id: PMID:34172445
title: Systemic regulation of mitochondria by germline proteostasis prevents protein aggregation in the soma of C. elegans.
findings:
- statement: Neuronal knockdown of cct-8 promotes polyQ67 aggregation in C. elegans neurons.
supporting_text: knockdown of cct-8 promotes neuronal polyQ67 aggregation
reference_review:
relevance: HIGH
correctness: VERIFIED
review_notes: >-
PubMed-verified C. elegans primary paper (full text available). Shows
cct-8 is required cell-autonomously to prevent neuronal polyglutamine
aggregation, corroborating its in-vivo folding/anti-aggregation role.
- id: PMID:19805813
title: A genomewide RNAi screen for genes that affect the stability, distribution and function of P granules in Caenorhabditis elegans.
findings:
- statement: >-
A genome-wide RNAi screen identified 173 P-granule genes; cct-8 was a hit,
and UniProt curates cct-8 as required for correct pgl-1 localization.
supporting_text: >-
we report on a genomewide RNAi screen in C. elegans, which identified 173
genes that affect the stability, localization, and function of P granules
reference_review:
relevance: HIGH
correctness: VERIFIED
review_notes: >-
PubMed-verified C. elegans primary paper (abstract-only in cache;
full_text_available:false). The abstract does not name cct-8 or pgl-1; the
specific pgl-1 localization requirement is from UniProt curation of the full
text (ECO:0000269 PubMed:19805813). Source of the worm-specific pgl-1 role.
- id: PMID:9851916
title: 'Genome sequence of the nematode C. elegans: a platform for investigating biology.'
findings: []
reference_review:
relevance: LOW
correctness: VERIFIED
review_notes: >-
Genome sequencing reference underlying the gene model (ORF Y55F3AR.3);
background only, does not address cct-8 function.
- id: file:interpro/panther/PTHR11353/PTHR11353-metadata.yaml
title: PANTHER family PTHR11353 (CHAPERONIN) metadata
findings:
- statement: cct-8 is classified in the PANTHER chaperonin family PTHR11353.
supporting_text: CHAPERONIN
- id: file:worm/cct-8/cct-8-uniprot.txt
title: UniProt record Q9N358 (TCPQ_CAEEL, T-complex protein 1 subunit theta)
findings:
- statement: cct-8 is required for correct subcellular localization of pgl-1.
supporting_text: Low and diffuse subcellular localization of pgl-1
- id: file:worm/cct-8/cct-8-deep-research-falcon.md
title: Falcon deep research synthesis for C. elegans cct-8
findings:
- statement: >-
Theta is a low-ATPase subunit that contributes substrate binding,
allostery, and assembly rather than bulk ATP consumption.
supporting_text: >-
CCT-8 occupies a defined position in the low-ATPase hemisphere and plays
a specialized role in substrate binding, allosteric regulation, and
complex assembly
tags:
- caeel-proteostasis