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The chaperonin containing TCP1 subunit 5 (CCT5) is believed to function as a tumor driver. However, a systematic pan-cancer analysis of CCT5 is still lacking. Therefore, this study aimed to identify the potential role of CCT5 in different types of tumors. This study comprehensively investigated the gene expression, proteomic expression, immune infiltration, DNA methylation, genetic alterations, correlation with TMB and MSI, drug sensitivity, enrichment analysis, and prognostic significance of CCT5 in 33 different tumors based on the TIMER2.0, GEPIA2, UALCAN, SMART, cBioPortal, GSCA databases, and TCGAplot R package. The results revealed significant CCT5 overexpression in most tumors and was significantly associated with poor OS and DFS in different tumor types. Reduced promoter and N-shore methylation of CCT5, indicating its potential oncogenic and epigenetic roles. Amplification was the most common type of CCT5 alterations. Immune infiltration analysis revealed a strong correlation between CCT5 and different immune cells. CCT5 exhibited a significant correlation with TMB and MSI in KIRC and STAD. Furthermore, enrichment analysis revealed associations between CCT5 and cell cycle pathway and various cellular functions. These findings suggested that CCT5 might serve as a potential prognostic biomarker and target for immunotherapy in various cancers.

Multiple sclerosis (MS) is a progressive, chronic, and highly disabling neuroinflammatory disorder characterized by demyelination and T cell-driven inflammation. Pathogenic T cells play a central role in MS, but effective therapeutic targeting remains challenging. Here, we identified ankyrin repeat domain-containing protein 55 (ANKRD55) as a key regulator of T cell function by single-cell transcriptomic analysis of cerebrospinal fluid and blood from MS patients. ANKRD55 was predominantly expressed in CD4+ T cells in both compartments. Genetic ablation of Ankrd55 led to a robustly reduced disease severity and neuroinflammation in experimental autoimmune encephalomyelitis (EAE), a widely used animal model for MS. Furthermore, T cell-specific deficiency of Ankrd55 significantly impaired Th1 polarization and Th17 differentiation, reducing EAE pathogenicity. Mechanistically, we found that Ankrd55 deficiency disrupted T cell receptor (TCR) signaling integrity. We demonstrated that ANKRD55 regulates the formation of the immune synapse, an essential prerequisite for TCR activation, by interacting with subunits of the chaperonin-containing TCP1 (CCT) complex and modulating its activity, enhancing its assembly by competing with CCT5 for binding to TCP1, CCT3, and CCT6. This facilitates proper microtubule organization and TCR activation. These findings establish ANKRD55 as a critical regulator of TCR signaling and highlight its therapeutic potential in pathogenic T cell-driven autoimmune diseases.

Efficient proteostasis and immune evasion are both critical for tumor progression. The chaperonin TRiC/CCT complex, which mediates the folding of cytoskeletal and signaling proteins, has been associated with oncogenesis; however, the specific role of its subunit CCT4 in tumor-immune interactions remain unclear. To address this gap, we integrated transcriptomics, proteomics, genomics, epigenetics and immunogenomics data. A comprehensive pan-cancer analysis was conducted (including the expression patterns, clinical relevance, prognosis value, immune infiltration of pan-cancer). Then an in-depth analysis of lung adenocarcinoma (LUAD) was carried out through enrichment analysis and single-cell RNA sequencing, and verified through cell experiments. CCT4 was found to be aberrantly upregulated across a majority of tumor types, particularly in LUAD, where elevated expression was associated with advanced stage and inferior survival outcomes. High CCT4 levels were linked to reduced immune cell infiltration and diminished anti-tumor immune signaling, specifically manifested as increased Th2 cell infiltration and decreased Th1 and CD8 T-cell signatures. Single-cell analyses revealed coordinated overexpression of all CCT subunits in tumor epithelial cells, supporting a global TRiC activation. However, CCT4 was preferentially enriched within highly proliferative subclusters, suggesting partial subunit-specific regulation. CCT4 knockdown suppressed LUAD cell proliferation, migration, and invasion . CCT4 links enhanced proteostasis with immune evasion in LUAD, acting partly through TRiC complex activity and possibly through independent nuclear functions. These findings refine the understanding of how proteostatic machinery contributes to immune modulation in cancer and highlight CCT4 as a potential molecular node bridging tumor growth and immune suppression.

T cells rely for their development and function on the correct folding and turnover of proteins generated in response to a broad range of molecular cues. In the absence of the eukaryotic type II chaperonin complex, CCT, T cell activation induced changes in the proteome are compromised including the formation of nuclear actin filaments and the formation of a normal cell stress response. Consequently, thymocyte maturation and selection, and T cell homeostatic maintenance and receptor-mediated activation are severely impaired. In the absence of CCT-controlled protein folding, Th2 polarization diverges from normal differentiation with paradoxical continued IFN-γ expression. As a result, CCT-deficient T cells fail to generate an efficient immune protection against helminths as they are unable to sustain a coordinated recruitment of the innate and adaptive immune systems. These findings thus demonstrate that normal T cell biology is critically dependent on CCT-controlled proteostasis and that its absence is incompatible with protective immunity.Oftedal et al. generate mice lacking the chaperonin subunit CCT8 in T cells. They find that loss of CCT8 leads to reduced formation of nuclear actin filaments, changes in proteostasis, defective Th2 cell polarization and T cell metabolism and a failed antigenic response to intestinal helminths.

Abstract Both group I (HSP60) and group II (CCT) chaperonins are targets of autoantibodies. Autoimmune reactions to HSP60 have been well characterized, while immune reactions to group II chaperonin have not been clarified. Methanobrevibacter oralis is a suspected periodontal pathogen with group II chaperonin. In this study, serum responses to M. oralis chaperonin, human HSP60, and CCT subunits were examined using sera from patients with periodontitis and autoimmune diseases. In comparison with healthy controls, periodontitis patients showed significantly higher responses to CCT4 and CCT8 on dot blot analysis. Signals for CCT3 and CCT8 in autoimmune disease patients were significantly higher than in controls. Significant differences were also demonstrated by Western blotting in anti-CCT4 response in both patient groups. All subjects showed strong reactivity to M. oralis chaperonin and faint signals to human HSP60. Autoantibodies were raised against CCT rather than HSP60; and CCT3, CCT4, and CCT8 were shown to be the main targets. Host immune systems may be frequently exposed to chaperonins of Archaea in various habitats. Although further studies of the cross-reactivity between M. oralis chaperonin and human CCT are required, anti-CCT autoantibodies may be involved in the pathogenesis of periodontitis and autoimmune diseases. Methanobrevibacter oralis is a suspected periodontal pathogen and in this study the serum responses to human CCT and the M.oralis group II chaperonin were studied in patients with periodontitis and autoimmune diseases. Interestingly, both diseased groups showed elevated responses to one or more CCT subunits, suggesting the potential importance of cross-reactivity in autoimmune diseases.

Background: This study was attempted to identify new molecules expressed on the plasma membrane of human umbilical vein endothelial cells (HUVECs) using monoclonal antibody-based proteomics technology and to determine the effect of the identified antibody on vascular reactivity. Methods: Twenty-two antibodies were developed from rats inoculated with HUVECs, and their effects were determined by observing vascular reactivity. Results: Among the 22 antibodies, the C-7 antibody significantly inhibited endothelium-dependent vasorelaxation in response to acetylcholine (ACh) but not to histamine. Moreover, the C-7 antibody did not affect norepinephrine-induced contraction in either the endothelium-intact or -denuded aorta. A proteomics study involving immunoprecipitation of the C-7 antibody with biotinylated HUVECs showed that this antibody binds to plasma membrane proteins corresponding to immunoglobulin heavy chain (VHDJ region), chaperonin-containing T-complex polypeptide 1 and α-actinin 4. The muscarinic M3 ACh receptor and α-actinin 4 were colocalized on the plasma membrane of HUVECs, and the colocalization was found to increase in response to ACh and was inhibited by pretreatment with the C-7 antibody. Conclusions: These results demonstrate that monoclonal C-7 antibody exerts an inhibitory effect on endothelium-dependent vasorelaxation induced by ACh and that this response may at least partially result from the inhibition of α-actinin 4.

Studies on TCP1-1 ring complex (TRiC) chaperonin have shown its indispensable role in folding cytosolic proteins in eukaryotes. In a psychrophilic organism, extreme cold temperature creates a low-eneigy environment that potentially causes protein denaturation with loss of activity. We hypothesized that TRiC may undergo evolution in terms of its structural molecular adaptation in order to facilitate protein folding in low-energy environment. To test this hypothesis, we isolated G. antarctica TRiC (GaTRiC) and found that the expression of GaTRiC mRNA in G. antarctica was consistently expressed at all temperatures indicating their importance in cell regulation. Moreover, we showed GaTRiC has the ability of a chaperonin whereby denatured luciferase can be folded to the functional stage in its presence. Structurally, three categories of residue substitutions were found in α, β, and δ subunits: (i) bulky/polar side chains to alanine or valine, (ii) charged residues to alanine, and (iii) isoleucine to valine that would be expected to increase intramolecular flexibility within the GaTRiC. The residue substitutions observed in the built structures possibly affect the hydrophobic, hydrogen bonds, and ionic and aromatic interactions which lead to an increase in structural flexibility. Our structural and functional analysis explains some possible structural features which may contribute to cold adaptation of the psychrophilic TRiC folding chamber.

Background Chaperonin containing TCP1 subunit 5 (CCT5), a vital component of the molecular chaperonin complex, has been implicated in tumorigenesis, cancer stemness maintenance, and therapeutic resistance. Nevertheless, its comprehensive roles in pan-cancer progression, underlying biological functions, and potential as a predictor of immunotherapy response remains poorly understood. Methods We performed a comprehensive multi-omics pan-cancer analysis of CCT5 across 33 cancer types, integrating bulk RNA-seq, single-cell RNA-seq (scRNA-seq), and spatial transcriptomics data. CCT5 expression patterns, prognostic relevance, stemness association, and immune microenvironment relationships were evaluated. A novel CCT5-based signature (CCT5.Sig) was developed using machine learning on 23 immune checkpoint blockade (ICB) cohorts ( n  = 1394) spanning eight cancer types. Model performance was assessed using AUC metrics and survival analyses. Results CCT5 was significantly overexpressed in tumor tissues and primarily localized to malignant and cycling cells. High CCT5 expression correlated with poor prognosis in multiple cancers and was enriched in oncogenic, cell cycle, and DNA damage repair pathways. CCT5 expression was positively associated with mRNAsi, mDNAsi, and CytoTRACE scores, indicating a role in stemness maintenance. Furthermore, CCT5-high tumors exhibited immune-cold phenotypes, with reduced TILs and CD8⁺ T cell activity. The CCT5.Sig model, based on genes co-expressed with CCT5, achieved superior predictive accuracy for ICB response (AUC = 0.82 in validation and 0.76 in independent testing), outperforming existing pan-cancer signatures. Conclusion This study reveals the multifaceted oncogenic roles of CCT5 and highlights its potential as a pan-cancer biomarker for prognosis and immunotherapy response. The machine learning-derived CCT5.Sig model provides a robust tool for patient stratification and may inform personalized immunotherapy strategies. Graphical abstract

Sorafenib is widely used in treating advanced hepatocellular carcinoma (HCC). However, its effectiveness in prolonging patient survival is limited by the development of drug resistance. To systematically investigate the resistance mechanisms of Sorafenib, an integrative analysis combining posttranslational modification (PTM) omics and CRISPR/Cas9 knockout library screening was conducted. This analysis identified ubiquitination at lysine 21 (K21) on chaperonin-containing TCP1 subunit 3 (CCT3) as being associated with Sorafenib resistance. Transcriptomic data from HCC patients treated with Sorafenib revealed that CCT3 expression was lower in responders compared to non-responders. Experimentally, inhibiting the expression of CCT3 sensitized HCC cells to Sorafenib and enhanced Sorafenib-induced ferroptosis. Additionally, CCT3 was found to interact with ACTN4, hindering the recycling of transferrin receptor protein 1 (TFRC) to the cell membrane, thus obstructing iron endocytosis. Mechanistically, the inhibition of ferroptosis by CCT3 depends on the deubiquitination of K6-linked non-degradative ubiquitination at its K21, which occurs upon Sorafenib treatment. Moreover, CCT3 knockdown enhanced the anti-tumor effects of Sorafenib in nude mice. In summary, we have identified a novel function of the chaperone protein. Targeting the CCT3/ACTN4/TFRC axis offers a promising strategy to enhance ferroptosis and overcome Sorafenib resistance in HCC.

Diffuse large B-cell lymphoma (DLBCL), an invasive lymphoma with substantial heterogeneity, can be mainly categorised into germinal centre B-cell-like (GCB) and non-GCB subtypes. DLBCL cells are highly susceptible to ferroptosis, which offers an effective avenue for treating recurrent and refractory DLBCL. Moreover, various heat shock proteins are involved in regulating the sensitivity of tumour cells to ferroptosis. Among these proteins, tailless complex polypeptide 1 (TCP1), a subunit of chaperonin-containing T-complex protein-1 (CCT), plays a role in tumour proliferation and survival. Therefore, we explored the role of TCP1 in different DLBCL subtypes, the sensitivity of GCB and non-GCB subtypes to the ferroptosis inducer RAS-selective lethal small molecule 3 (RSL3), and the underlying molecular mechanism. In GCB cells, TCP1 promoted RSL3-induced ferroptosis. Notably, TCP1 could bind with acyl-CoA synthetase long-chain family member 4 (ACSL4), a key enzyme regulating lipid composition and facilitating ferroptosis, to reduce its ubiquitination and degradation. This interaction activated the ACSL4/LPCAT3 signalling pathway and promoted ferroptosis in the GCB subtype. However, in the non-GCB subtype, TCP1 did not act as a positive regulator but served as a predictor of an unfavourable prognosis in patients with non-GCB. In conclusion, our results suggest that in DLBCL, high TCP1 expression enhances the sensitivity of GCB tumour cells to ferroptosis and serves as a marker of poor prognosis in patients with non-GCB DLBCL.