The chaperonin CCT8 controls proteostasis essential for T cell maturation, selection, and function

Oftedal, Bergithe E.; Maio, Stefano; Handel, Adam E.; Mpj., White; Howie, Duncan; Davis, Simon; Prevot, Nicolas; Rota, Ioanna A.; Deadman, Mary E.; Kessler, Benedikt M.; Fischer, Román; Trede, Nikolaus S.; Sezgin, Erdinç; Maizels, Rick M.; Holländer, G A

doi:10.1038/s42003-021-02203-0

Cited by 9 publications

(9 citation statements)

References 76 publications

(87 reference statements)

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“…Bergithe’s studies had shown that Th2 cell polarization and T-cell metabolism are dependent on CCT8 expression, 32 but no research has reported the effect of CCT8 on tumor-infiltrating lymphocytes (TILs). Our study firstly demonstrated that CCT8 expression was positively correlated with CD4+ Th2 cell infiltration in the vast majority of TCGA cancers.…”

Section: Discussionmentioning

confidence: 99%

Multi-Omics Analysis and Verification of the Oncogenic Value of CCT8 in Pan-Cancers

Gong¹,

Zhong²,

Gong³

et al. 2023

JIR

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Background Chaperonin-containing TCP1 subunit 8 (CCT8) has been proved to be involved in the occurrence and development of some cancers. However, no study has reported the potential role of CCT8 in a pan-cancer manner. Methods TIMER2.0, GEPIA2, UALCAN and Sangerbox were used to explore the expression, prognosis and methylation of CCT8. We used cBioPortal, TISIDB, SangerBox, TIMER2.0 and TISMO to investigate the genetic alteration of CCT8 and the relationship of CCT8 with molecular subtype, immune subtype, immune infiltration and immunotherapy response. CCT8-related genes were screened out through GEPIA and STRING for Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis. CCK-8, the colony formation assay, the wound healing assay and the Transwell assay were performed to explore the influence of CCT8 on proliferation and migration. Results CCT8 was highly expressed in most cancers with a poor prognosis. The expression level of CCT8, which was affected by the promoter region methylation and genetic alteration, was related to the molecular and immune subtype of cancers. Interestingly, CCT8 was positively associated with the activated CD4 T cells and type 2 T-helper cells. CCT8 played a vital role in the cell cycle and RNA transport of cancers, and it significantly inhibited the proliferation and migration of lung adenocarcinoma cells when it was knocked down. Conclusion CCT8 plays an indispensable role in promoting the proliferation and migration of many cancers. CCT8 might be a biomarker of T-helper type 2 (Th2) cell infiltration and a promising therapeutic target for T-helper type 1(Th1)/Th2 imbalance.

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Section: Discussionmentioning

confidence: 99%

Multi-Omics Analysis and Verification of the Oncogenic Value of CCT8 in Pan-Cancers

Gong¹,

Zhong²,

Gong³

et al. 2023

JIR

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“…Folding of actin by CCT/TriC is another distinguished mechanism identi ed to be activated in CeD patients. CCT/TriC, as a molecular chaperone, is involved in the proper folding of up to 10% of newly synthesized proteins, including cytoskeleton components (21,22). Interestingly, actin as a major component of the cytoskeleton has been related to autoin ammatory diseases through the formation of misfolded structures (23).…”

Section: Discussionmentioning

confidence: 99%

Consensus Weighted Gene Co-expression Network Analysis demonstrates aberrations in folding of actin by CCT/TriC chaperonin family in Celiac disease

Fadaie

Khalafiyan

Ghafouri

et al. 2023

Preprint

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Background: Celiac disease (CeD) is an autoimmune enteropathy triggered by dietary gluten. Almost 90% of CeD patients have HLA-DQ2 or -DQ8 haplotypes. As a high proportion of first-degree relatives (FDRs) of CeD patients have the same haplotype, it is assumed that they are at a higher risk of disease development than the general population. Nevertheless, the prevalence of CeD among FDRs is considerably low (7.5%). Methods: In order to figure out this discrepancy, a microarray dataset of intestinal mucosal biopsies from CeD, FDR, and control groups was reanalyzed, and gene co-expression network using WGCNA was constructed. The differentially expressed genes in the opposite modules from the consensus analysis were applied for functional enrichment analysis. Results: WGCNA analysis identified 10 consensus modules in both CeD and FDR groups, including 5 modules with opposite correlation. Among the genes of opposing modules, 159 of them were identified as commonly differentially expressed genes with an adjusted p-value< 0.05 between FDR and CeD groups. Functional enrichment analysis revealed the significant contributions of these genes in host energy metabolism, programmed cell death, antigen cross presentation, and actin folding. In a deep view to the relation of actin folding to celiac disease occurrence, it was found that misfolding of actin and presentation of anti-actin antibodies occur in CeD patients. The current study reports that this pathway is oppositely regulated in FDR group and this might be a trigger for celiac manifestation. Conclusions: The consensus signaling pathways with opposing expression patterns identified in this study give us a clue about the gene circuits that are dysregulated in celiac patients. Considering the prominent relation of actin folding to disease occurrence and its opposite manner in celiac patients and healthy individuals, it is proposed that targeting CCT/TriC chaperonin family might result in a reduction of misfolded actin and the production of autoantibodies.

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“…CCT8 is a circRNA and is a member of the TCP-1 chaperone protein (CCT) family of genes. The chaperonin CCT8 controls proteostasis essential for T cell maturation, selection, and function ( Oftedal et al, 2021 ). Current studies have found that CCT8 was overexpressed in cancer, but no study so far has reported any association of CCT8 with asthma.…”

Section: Discussionmentioning

confidence: 99%

Construction of Severe Eosinophilic Asthma Related Competing Endogenous RNA Network by Weighted Gene Co-Expression Network Analysis

Wang

Zhang

et al. 2022

Front. Pharmacol.

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Background: Currently, disease control in patients with severe eosinophilic asthma is not optimistic. Competing endogenous RNA (ceRNA) networks have been found to play a key role in asthma in recent years. However, it is unclear whether ceRNA networks play an important part in severe eosinophilic asthma.Methods: Firstly, gene expression profiles related to severe eosinophilic asthma were downloaded from the Gene Expression Omnibus (GEO) database. Secondly, the key modules were identified by the weighted gene co-expression network analysis (WGCNA). Thirdly, genes in modules highly associated with severe eosinophilic asthma were selected for further construction of the ceRNA network. Fourthly, Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses were performed on hub genes. Finally, the results of this study were validated on the GSE143303, GSE137268, and GSE147878 datasets.Results: 22 severe eosinophilic asthmatics and 13 healthy controls were extracted for WGCNA. We found that the genes in the black module (r = −0.75, p < 0.05) and yellow module (r = 0.65, p < 0.05) were highly associated with severe eosinophilic asthma. EP300 was discovered to serve the key connecting function in the ceRNA network. Surprisingly, lncRNAs seem to eliminate the role of EP300 in the black module and we discovered that CCT8 and miRNA-mRNA formed a circRNA-miRNA-mRNA network in the yellow module. We found that EP300 and FOXO3 in the black module were regulated by steroid hormones in the enrichment analysis, which were related to the medication used by the patient. Through validation of other datasets, we found that the hub genes in the yellow module were the key genes in the treatment of severe eosinophilic asthma. In particular, RPL17 and HNRNPK might specifically regulate severe eosinophilic asthma.Conclusion: RPL17 and HNRNPK might particularly regulate severe eosinophilic asthma. Our results could be useful to provide potential immunotherapy targets and prognostic markers for severe eosinophilic asthma.

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The chaperonin CCT8 controls proteostasis essential for T cell maturation, selection, and function

Cited by 9 publications

References 76 publications

Multi-Omics Analysis and Verification of the Oncogenic Value of CCT8 in Pan-Cancers

Multi-Omics Analysis and Verification of the Oncogenic Value of CCT8 in Pan-Cancers

Consensus Weighted Gene Co-expression Network Analysis demonstrates aberrations in folding of actin by CCT/TriC chaperonin family in Celiac disease

Construction of Severe Eosinophilic Asthma Related Competing Endogenous RNA Network by Weighted Gene Co-Expression Network Analysis

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