CCT6A facilitates lung adenocarcinoma progression and glycolysis via STAT1/HK2 axis.

BACKGROUND: Chaperonin Containing TCP1 Subunit 6 A (CCT6A) is a prominent protein involved in the folding and stabilization of newly synthesized proteins. However, its roles and underlying mechanisms in lung adenocarcinoma (LUAD), one of the most aggressive cancers, remain elusive. METHODS: Our study utilized in vitro cell phenotype experiments to assess CCT6A's impact on the proliferation and invasion capabilities of LUAD cell lines. To delve into CCT6A's intrinsic mechanisms affecting glycolysis and proliferation in lung adenocarcinoma, we employed transcriptomic sequencing and liquid chromatography-mass spectrometry analysis. Co-immunoprecipitation (Co-IP) and chromatin immunoprecipitation (CHIP) assays were also conducted to substantiate the mechanism. RESULTS: CCT6A was found to be significantly overexpressed in LUAD and associated with a poorer prognosis. The silencing of CCT6A inhibited the proliferation and migration of LUAD cells and elevated apoptosis rates. Mechanistically, CCT6A interacted with STAT1 protein, forming a complex that enhances the stability of STAT1 by protecting it from ubiquitin-mediated degradation. This, in turn, facilitated the transcription of hexokinase 2 (HK2), a critical enzyme in aerobic glycolysis, thereby stimulating LUAD's aerobic glycolysis and progression. CONCLUSION: Our findings reveal that the CCT6A/STAT1/HK2 axis orchestrated a reprogramming of glucose metabolism and thus promoted LUAD progression. These insights position CCT6A as a promising candidate for therapeutic intervention in LUAD treatment.

CCT6A alleviates pulmonary fibrosis by inhibiting HIF-1α-mediated lactate production.

Idiopathic pulmonary fibrosis (IPF) is a lethal progressive fibrotic lung disease. The development of IPF involves different molecular and cellular processes, and recent studies indicate that lactate plays a significant role in promoting the progression of the disease. Nevertheless, the mechanism by which lactate metabolism is regulated and the downstream effects remain unclear. The molecular chaperone CCT6A performs multiple functions in a variety of biological processes. Our research has identified a potential association between CCT6A and serum lactate levels in IPF patients. Herein, we found that CCT6A was highly expressed in type 2 alveolar epithelial cells (AEC2s) of fibrotic lung tissues and correlated with disease severity. Lactate increases the accumulation of lipid droplets in epithelial cells. CCT6A inhibits lipid synthesis by blocking the production of lactate in AEC2s and alleviates bleomycin-induced pulmonary fibrosis in mice. In addition, our results revealed that CCT6A blocks HIF-1α-mediated lactate production by driving the VHL-dependent ubiquitination and degradation of HIF-1α and further inhibits lipid accumulation in fibrotic lungs. In conclusion, we propose that there is a pivotal regulatory role of CCT6A in lactate metabolism in pulmonary fibrosis, and strategies aimed at targeting these key molecules could represent potential therapeutic approaches for pulmonary fibrosis.

CCT6A dysregulation in surgical prostate cancer patients: association with disease features, treatment information, and prognosis.

OBJECTIVE: Chaperonin-containing tailless complex polypeptide 1 subunit 6A (CCT6A) involves several solid cancers' development and progression, while its clinical utility in prostate cancer management is rarely revealed. Consequently, the present study intended to investigate the linkage of CCT6A with disease features, treatment information, and prognosis of surgical prostate cancer patients. METHODS: CCT6A in 220 surgical prostate cancer patients was determined via immunohistochemistry. Additionally, survival analyses on data from the public databases were performed to validate the prognostic value of CCT6A further. RESULTS: CCT6A expression was upregulated in tumor tissue than in adjacent tissue (P < 0.001). Increased CCT6A was related to elevated Gleason score (P < 0.001) and pathological T stage (P = 0.029). CCT6A was increased in patients with positive surgical margin status (vs. negative) (P = 0.029) and patients with adjuvant external-beam radiation therapy (vs. no) (P = 0.001). Concerning the prognostic value, high tumor CCT6A was linked with shortened disease-free survival (DFS) (P = 0.009), which was also validated through further Cox's proportional hazard regression model analyses (hazard ratio: 2.695, 95% CI: 1.086-6.683, P = 0.032), whereas CCT6A was not correlated with overall survival (OS) (P > 0.050). Additionally, the Gene Expression Profiling Interactive Analysis database indicated that high tumor CCT6A was related to shortened DFS (P = 0.036), but it was not associated with OS (P > 0.050); meanwhile, the Human Protein Atlas database suggested that high tumor CCT6A was linked with reduced OS (P = 0.048). CONCLUSION: Tumor CCT6A high expression correlates with the elevated Gleason score, pathological T stage, and shortened DFS in surgical prostate cancer patients.

Chaperonin containing TCP1 subunit 6A may activate Notch and Wnt pathways to facilitate the malignant behaviors and cancer stemness in oral squamous cell carcinoma.

Chaperonin containing TCP1 subunit 6A (CCT6A) was recently discovered to be involved in cancer pathogenesis and stemness; however, its role in oral squamous cell carcinoma (OSCC) has not been reported. The current study aimed to investigate the impact of CCT6A on OSCC cell malignant behaviors and stemness and to explore its potentially interreacted pathways. SCC-15 and HSC-3 cells were transfected with the plasmid loading control overexpression, CCT6A overexpression, control knockout, or CCT6A knockout. Wnt4 overexpression or Notch1 overexpression plasmids were transfected into CCT6A-knockout SCC-15 cells. Cell proliferation, apoptosis, invasion, stemness, Notch, and Wnt pathways were detected in both cell lines, whereas RNA sequencing was only performed in SCC-15 cells. CCT6A was upregulated in five OSCC cell lines, including SCC-15, HSC-3, SAT, SCC-9, and KON, compared to that in the control cell line. In SCC-15 and HSC-3 cells, CCT6A overexpression increased cell proliferation, invasion, sphere formation, CD133, and Sox2 expression, but decreased cell apoptosis; on the contrary, CCT6A knockout exhibited an opposite effect on the above indexes. RNA-sequencing data revealed that the Wnt and Notch pathways were involved in the CCT6A'effect on SCC-15 cell functions. CCT6A positively regulates the Wnt and Notch pathways in SCC-15 and HSC-3 cells. Importantly, it was shown that activation of the Wnt or Notch pathways attenuated the effect of CCT6A knockout on SCC-15 cell survival, invasion, and stemness. CCT6A may promote OSCC malignant behavior and stemness by activating the Wnt and Notch pathways.

CCT6A is associated with CDC20, Enneking stage and prognosis in osteosarcoma, and its knockdown suppresses osteosarcoma cell viability and invasion.

Chaperonin-containing tailless complex polypeptide 1 subunit 6A (CCT6A) regulates the proliferation, invasiveness and stemness of numerous types of cancer, and may interact with cell division cycle 20 (CDC20); however, its implication in osteosarcoma remains unclear. The present study aimed to investigate the relationship between CCT6A and CDC20, and their association with clinical features and prognosis. Subsequently, the present study explored the effects of their knockdown on osteosarcoma cell malignant behaviors. A total of 52 patients with osteosarcoma underwent tumor resection were retrospectively analyzed. CCT6A and CDC20 expression levels in tumor and nontumor tissues were detected by reverse transcription-quantitative PCR and immunohistochemistry. In addition, CCT6A and CDC20 small interfering RNA molecules were transfected into osteosarcoma cell lines. The results revealed that the mRNA (P<0.001) and protein (P<0.001) expression levels of CCT6A were elevated in tumor tissues compared with those in nontumor tissues. Tumor CCT6A mRNA expression was correlated with elevated CDC20 mRNA expression (P<0.001), higher Enneking stage (P=0.039), abnormal lactate dehydrogenase (LDH) level (>300 U/l) (P=0.048), lower pathological response (P=0.024) and worse disease-free survival (DFS) (P=0.015). Tumor CCT6A protein expression was also associated with increased CDC20 protein (P<0.001), elevated Enneking stage (P=0.005), abnormal LDH (P=0.019), decreased pathological response (P=0.014), shorter DFS (P=0.030) and overall survival (OS) (P=0.027). After adjustment by multivariate Cox analyses, tumor CCT6A mRNA expression was shown to independently predict lower pathological response (P=0.033) and poor DFS (P=0.028), but not OS. Regarding CDC20, it was associated with a higher Enneking stage and lower pathological response (both P<0.05), whereas it failed to estimate DFS or OS. In vitro experiments demonstrated that CCT6A and CDC20 knockdown inhibited proliferation and invasion, and enhanced apoptosis in U-2 OS and Saos-2 cells (all P<0.05). In conclusion, CCT6A is associated with CDC20, Enneking stage and prognosis of osteosarcoma, and its knockdown decreases the viability and invasion of osteosarcoma cells.

CCT6A promotes esophageal squamous cell carcinoma cell proliferation, invasion and epithelial-mesenchymal transition by activating TGF-ß/Smad/c-Myc pathway.

OBJECTIVE: Chaperonin-containing TCP1 subunit 6A (CCT6A) facilitates several malignant cancer behaviors, but its regulation of esophageal squamous cell carcinoma (ESCC) has not been reported. This study aimed to investigate the effect of CCT6A on cell proliferation, apoptosis, invasion and epithelial-mesenchymal transition (EMT) and its interaction with the TGF-ß/Smad/c-Myc pathway in ESCC. METHODS: CCT6A expression was detected in ESCC and normal esophageal epithelial cell lines by RT‒qPCR and western blotting. Furthermore, CCT6A siRNA, negative control (NC) siRNA, CCT6A encoding plasmid and NC encoding plasmid were transfected into OE21 and TE-1 cells. Subsequently, CCT6A siRNA- and NC siRNA-transfected cells were treated with TGF-ß for rescue experiments. Cell proliferation, apoptosis, invasion, and E-cadherin/N-cadherin and p-Smad2/p-Smad3/c-Myc expression were detected. RESULTS: CCT6A expression was increased in KYSE-180, TE-1, TE-4 and OE21 cells compared with HET-1A cells. In both OE21 and TE-1 cells, CCT6A knockdown inhibited cell proliferation, invasion and N-cadherin expression while promoting cell apoptosis and E-cadherin expression; meanwhile, CCT6A overexpression had the opposite effects. Furthermore, in both OE21 and TE-1 cells, CCT6A knockdown decreased p-Smad2/Smad2, p-Smad3/Smad3 and c-Myc/GAPDH expression; CCT6A overexpression had the opposite effects. Next, TGF-ß facilitated cell proliferation, invasion, and N-cadherin, p-Smad2/Smad2, p-Smad3/Smad2 and c-Myc/GAPDH expression while repressing cell apoptosis and E-cadherin expression in OE21 and TE-1 cells; importantly, TGF-ß could compensate for the regulation of CCT6A knockdown on these activities. CONCLUSION: CCT6A facilitates ESCC malignant activities by activating the TGF-ß/Smad/c-Myc pathway, which sheds light on the identification of a possible therapeutic target in the management of ESCC.

Progress of expression and function of messenger RNA CCT6A in malignancies / 肿瘤研究与临床

Messenger RNA(mRNA) CCT6A can encode chaperone proteins and plays an important role in malignant tumors such as colorectal cancer, lung cancer and breast cancer. CCT6A is highly expressed in malignant tumors, which can be used as a biomarker to assess patients' prognosis, and promote malignant biological behaviors such as tumor proliferation and metastasis by regulating transforming growth factor β signals, cell cycles, and other pathways. CCT6A can also modulate immune cell infiltration in the tumor microenvironment and may be a potential target for tumor immunotherapy. The paper reviews the expression and function of CCT6A in malignancies.

The intercorrelation among CCT6A, CDC20, CCNB1, and PLK1 expressions and their clinical value in papillary thyroid carcinoma prognostication.

BACKGROUND: CCT6A promotes several carcinomas' growth and invasion in multiple ways, and it relates to CCNB1 and PLK1 through its interaction with CDC20 via protein-protein interaction bioinformatics. This study aimed to explore the intercorrelation among CCT6A, CDC20, CCNB1, and PLK1, and their association with tumor features and prognosis in papillary thyroid carcinoma (PTC) patients. METHODS: CCT6A, CDC20, CCNB1, and PLK1 expressions in 186 tumor and 30 non-tumor specimens from PTC patients were determined by immunohistochemical (IHC). Clinical features, disease-free survival (DFS), and overall survival (OS) were retrieved. RESULTS: CCT6A, CDC20, CCNB1, and PLK1 expressions were upregulated in tumor tissues compared with non-tumor tissues (all p < 0.001). CCT6A expression positively correlated with CDC20, CCNB1, and PLK1 expressions; besides, CDC20 expression positively associated with CCNB1 and PLK1 expressions, and CCNB1 expression was also positively related to PLK1 expression (all p < 0.05). Moreover, elevated tumor CCT6A expression was correlated with extrathyroidal invasion (p = 0.015), higher pT stage (p < 0.001), pN stage (p = 0.046), and pTNM stage (p = 0.042); while tumor CDC20, CCNB1, and PLK1 expressions only correlated with some of these indexes (most p < 0.05). Notably, CCT6A and CDC20 high expressions predicted worse DFS and OS (all p < 0.05); CCNB1 positive expression only predicted poor DFS (p = 0.044) but not OS (p = 0.152); however, PLK1 expression failed to predict these two indexes (both p > 0.05). After adjustment using multivariate Cox's regression, CCT6A expression (high vs. low) independently estimated shorter DFS (p = 0.010) and OS (p = 0.006). CONCLUSION: CCT6A, CDC20, CCNB1, and PLK1 are intercorrelated, and they exhibit certain prognostic values in PTC patients.

Identifying Candidate Protein Markers of Acute Kidney Injury in Acute Decompensated Heart Failure.

One-quarter of patients with acute decompensated heart failure (ADHF) experience acute kidney injury (AKI)-an abrupt reduction or loss of kidney function associated with increased long-term mortality. There is a critical need to identify early and real-time markers of AKI in ADHF; however, to date, no protein biomarkers have exhibited sufficient diagnostic or prognostic performance for widespread clinical uptake. We aimed to identify novel protein biomarkers of AKI associated with ADHF by quantifying changes in protein abundance in the kidneys that occur during ADHF development and recovery in an ovine model. Relative quantitative protein profiling was performed using sequential window acquisition of all theoretical fragment ion spectra-mass spectrometry (SWATH-MS) in kidney cortices from control sheep (n = 5), sheep with established rapid-pacing-induced ADHF (n = 8), and sheep after ~4 weeks recovery from ADHF (n = 7). Of the 790 proteins quantified, we identified 17 candidate kidney injury markers in ADHF, 1 potential kidney marker of ADHF recovery, and 2 potential markers of long-term renal impairment (differential abundance between groups of 1.2-2.6-fold, adjusted p < 0.05). Among these 20 candidate protein markers of kidney injury were 6 candidates supported by existing evidence and 14 novel candidates not previously implicated in AKI. Proteins of differential abundance were enriched in pro-inflammatory signalling pathways: glycoprotein VI (activated during ADHF development; adjusted p < 0.01) and acute phase response (repressed during recovery from ADHF; adjusted p < 0.01). New biomarkers for the early detection of AKI in ADHF may help us to evaluate effective treatment strategies to prevent mortality and improve outcomes for patients.

Chaperonins in cancer: Expression, function, and migration in extracellular vesicles.

The chaperonins CCT and Hsp60 are molecular chaperones, members of the chaperone system (CS). Chaperones are cytoprotective but if abnormal in quantity or quality they may cause diseases, the chaperonopathies. Here, recent advances in the understanding of CCT and Hsp60 in cancerology are briefly discussed, focusing on breast and brain cancers. CCT subunits, particularly CCT2, were increased in breast cancer cells and this correlated with tumor progression. Experimental induction of CCT2 increase was accompanied by an increase of CCT3, 4, and 5, providing another evidence for the interconnection between the members of the CS and the difficulties expected while manipulating one member with therapeutic purposes. Another in silico study demonstrated a direct correlation between the increase in the tumor tissue of the mRNA levels of all CCT subunits, except CCTB6, with bad prognosis. Studies with glioblastomas demonstrated an increase in the CCT subunits in the tumor tissue and in extracellular vesicles (EVs) derived from them. Expression levels of CCT1, 2, 6A, and 7 were the most increased and markers of bad prognosis, particularly CCT6A. A method for measuring Hsp60 and related miRNA in exosomes from blood of patients with glioblastomas or other brain tumors was discussed, and the results indicate that the triad Hsp60-related miRNAs-exosomes has potential regarding diagnosis and patient monitoring. All these data provide a strong foundation for future studies on the role played by chaperonins in carcinogenesis and for fully developing their theranostics applications along with exosomes.

Dynamic Network Biomarker of Pre-Exhausted CD8+ T Cells Contributed to T Cell Exhaustion in Colorectal Cancer.

Immunotherapy has achieved positive clinical responses in various cancers. However, in advanced colorectal cancer (CRC), immunotherapy is challenging because of the deterioration of T-cell exhaustion, the mechanism of which is still unclear. In this study, we depicted CD8+ T-cell developmental trajectories and characterized the pre-exhausted T cells isolated from CRC patients in the scRNA-seq data set using a dynamic network biomarker (DNB). Moreover, CCT6A identified by DNB was a biomarker for pre-exhausted T-cell subpopulation in CRC. Besides, TUBA1B expression was triggered by CCT6A as DNB core genes contributing to CD8+ T cell exhaustion, indicating that core genes serve as biomarkers in pre-exhausted T cells. Remarkably, both TUBA1B and CCT6A expressions were significantly associated with the overall survival of COAD patients in the TCGA database (p = 0.0082 and p = 0.026, respectively). We also observed that cellular communication between terminally differentiated exhausted T cells and pre-exhausted T cells contributes to exhaustion. These findings provide new insights into the mechanism of T-cell exhaustion and provide clue for targeted immunotherapy in CRC.

CCT6A may act as a potential biomarker reflecting tumor size, lymphatic metastasis, FIGO stage, and prognosis in cervical cancer patients.

OBJECTIVE: Chaperonin-containing tailless complex polypeptide subunit 6A (CCT6A) is a critical regulator and newly identified clinical biomarker of several cancers, while its correlation with the clinical characteristics and prognosis of cervical cancer patients is unclear. Therefore, this study aimed to explore this issue. METHODS: Chaperonin-containing tailless complex polypeptide subunit 6A expression in tumor and tumor-adjacent tissues from 198 cervical cancer patients who underwent resection were detected by immunohistochemistry assay and reverse transcription-quantitative polymerase chain reaction. Besides, the clinicopathological features and survival data of cervical cancer patients were collected. RESULTS: Chaperonin-containing tailless complex polypeptide subunit 6A protein and mRNA levels were both increased in tumor tissues compared with tumor-adjacent tissues (both p < 0.001). Receiver operating characteristic curves showed that CCT6A protein (AUC: 0.774, 95% CI: 0.729-0.819) and mRNA levels (AUC: 0.904, 95% CI: 0.874-0.934) well discriminated tumor tissues from tumor-adjacent tissues. Besides, correlation analyses found that CCT6A protein and mRNA levels were positively correlated with lymph node metastasis and FIGO stage (all p < 0.05), apart from which CCT6A mRNA level was also positively associated with tumor size (p = 0.032). In addition, CCT6A protein and mRNA levels were negatively correlated with accumulating disease-free survival (both p < 0.05); meanwhile CCT6A mRNA level was negatively associated with accumulating overall survival as well (p = 0.010). CONCLUSION: Chaperonin-containing tailless complex polypeptide subunit 6A is elevated in tumor tissues, and its high expression associates with larger tumor size, lymph node metastasis, higher FIGO stage, and worse prognosis in cervical cancer patients.

Long non-coding RNA NEAT1 promotes human glioma tumor progression via miR-152-3p/CCT6A pathway.

BACKGROUND: Long non-coding RNA (lncRNA) nuclear enriched abundant transcript 1 (NEAT1) has been documented to implicate in diverse tumor progression. However, the mechanism of NEAT1 in glioma was rarely reported. METHODS: The levels of NEAT1, microRNA-152-3p (miR-152-3p) and chaperonin containing TCP1 subunit 6A (CCT6A) in glioma tissues and cells were measured by quantitative real-time polymerase chain reaction (qRT-PCR). The cell viability, apoptotic rate, the migrated and invaded abilities of A172 and U251 cells were evaluated via cell counting kit-8 (CCK-8), flow cytometry and Transwell assay, respectively. The mice xenograft model was constructed to further verify the effect of NEAT1. The interactions between miR-152-3p and NEAT1 or CCT6A were predicted by starBase v2.0 or TargetScan, then luciferase reporter assay, RNA immunoprecipitation (RIP) and RNA pull-down assay were performed to validate the interaction. The protein level of CCT6A was detected by Western blot assay. RESULTS: The levels of NEAT1, CCT6A were highly expressed, but miR-152-3p was decreased in glioma tissues and cells. NEAT1 depletion or miR-152-3p mimics suppressed cell viability, migrated and invaded abilities but induced apoptotic rate in A172 and U251 cells, while the introduction of CCT6A partly counteracted these impacts. In addition, NEAT1 silencing impeded xenograft tumor growth in vivo. MiR-152-3p was verified as a direct target of NEAT1 and directly targeted CCT6A. CCT6A expression was upregulated by NEAT1 and reversed by miR-152-3p. CONCLUSION: NEAT1 enhanced glioma progression, partially through miR-152-3p/CCT6A pathway. The novel regulatory network might contribute to the diagnosis and treatment of glioma.

Overexpressing CCT6A Contributes To Cancer Cell Growth By Affecting The G1-To-S Phase Transition And Predicts A Negative Prognosis In Hepatocellular Carcinoma.

PURPOSE: To determine the oncogenic role of the sixth subunit of chaperonin-containing tailless complex polypeptide 1 (CCT6A) in hepatocellular carcinoma (HCC) and address the correlation of CCT6A with clinicopathological characteristics and survival. Additionally, this study aimed to explore the effect of CCT6A on HCC cells and the underlying mechanisms. METHODS: We searched for levels of CCT6A expression in the Oncomine database and GEPIA database, which was then validated by analyzing cancer and adjacent non-cancerous tissues of HCC patients using quantitative PCR, Western blot, and immunohistochemistry assays. The relationship between CCT6A expression and survival was analyzed from the GEPIA database and confirmed by immunohistochemistry assays of 133 HCC tissue sections. In addition, the effect of depleting CCT6A on cell proliferation was assessed by CCK-8 and colony formation assays. Cell cycle analysis, immunofluorescence assays, GSEA analysis, and cyclin D expression analyzed by Western blot were used to explore the possible underlying mechanism how dysregulated CCT6A affect the proliferation of HCC. RESULTS: Both mRNA and protein levels of CCT6A were increased in HCC tissues. Higher CCT6A expression was significantly associated with reduced overall survival (P = 0.023). CCT6A depletion inhibited cell proliferation and downregulated cyclin D, hindering the G1-to-S phase arrest. CONCLUSION: CCT6A may contribute to HCC cell proliferation by accelerating the G1-to-S transition, as it maintains the expression of cyclin D. CCT6A could be considered an oncogene of HCC and could be used as a prognostic biomarker for HCC.

Extracellular Vesicles from Neurosurgical Aspirates Identifies Chaperonin Containing TCP1 Subunit 6A as a Potential Glioblastoma Biomarker with Prognostic Significance.

Glioblastoma, WHO-grade IV glioma, carries a dismal prognosis owing to its infiltrative growth and limited treatment options. Glioblastoma-derived extracellular vesicles (EVs; 30-1000 nm membranous particles) influence the microenvironment to mediate tumor aggressiveness and carry oncogenic cargo across the blood-brain barrier into the circulation. As such, EVs are biomarker reservoirs with enormous potential for assessing glioblastoma tumors in situ. Neurosurgical aspirates are rich sources of EVs, isolated directly from glioma microenvironments. EV proteomes enriched from glioblastoma (n = 15) and glioma grade II-III (n = 7) aspirates are compared and 298 differentially-abundant proteins (p-value < 0.00496) are identified using quantitative LC-MS/MS. Along with previously reported glioblastoma-associated biomarkers, levels of all eight subunits of the key molecular chaperone, T-complex protein 1 Ring complex (TRiC), are higher in glioblastoma-EVs, including CCT2, CCT3, CCT5, CCT6A, CCT7, and TCP1 (p < 0.00496). Analogous increases in TRiC transcript levels and DNA copy numbers are detected in silico; CCT6A has the greatest induction of expression and amplification in glioblastoma and shows a negative association with survival (p = 0.006). CCT6A is co-localized with EGFR at 7p11.2, with a strong tendency for co-amplification (p < 0.001). Immunohistochemistry corroborates the CCT6A proteomics measurements and indicated a potential link between EGFR and CCT6A tissue expression. Putative EV-biomarkers described here should be further assessed in peripheral blood.

Chaperonin-containing T-complex Protein 1 Subunit ζ Serves as an Autoantigen Recognized by Human Vδ2 γδ T Cells in Autoimmune Diseases.

Human γδ T cells recognize conserved endogenous and stress-induced antigens typically associated with autoimmune diseases. However, the role of γδ T cells in autoimmune diseases is not clear. Few autoimmune disease-related antigens recognized by T cell receptor (TCR) γδ have been defined. In this study, we compared Vδ2 TCR complementarity-determining region 3 (CDR3) between systemic lupus erythematosus (SLE) patients and healthy donors. Results show that CDR3 length distribution differed significantly and displayed oligoclonal characteristics in SLE patients when compared with healthy donors. We found no difference in the frequency of Jδ gene fragment usage between these two groups. According to the dominant CDR3δ sequences in SLE patients, synthesized SL2 peptides specifically bound to human renal proximal tubular epithelial cell line HK-2; SL2-Vm, a mutant V sequence of SL2, did not bind. We identified the putative protein ligand chaperonin-containing T-complex protein 1 subunit ζ (CCT6A) using SL2 as a probe in HK-2 cell protein extracts by affinity chromatography and liquid chromatography-electrospray ionization-tandem mass spectrometry analysis. We found CCT6A expression on the surface of HK-2 cells. Cytotoxicity of only Vδ2 γδ T cells to HK-2 cells was blocked by anti-CCT6A antibody. Finally, we note that CCT6A concentration was significantly increased in plasma of SLE and rheumatoid arthritis patients. These data suggest that CCT6A is a novel autoantigen recognized by Vδ2 γδ T cells, which deepens our understanding of mechanisms in autoimmune diseases.

De novo 393 kb microdeletion of 7p11.2 characterized by aCGH in a boy with psychomotor retardation and dysmorphic features.

We report on a 27 month old boy presenting with psychomotor delay and dysmorphic features, mainly mild facial asymmetry, prominent cup-shaped ears, long eyelashes, open mouth appearance and slight abnormalities of the hands and feet. Array comparative genomic hybridization revealed a 393 kb microdeletion in 7p11.2. We discuss the possible involvement of CHCHD2, GBAS, MRPS17, SEPT14 and PSPH on our patient's phenotype. Additionally, we studied the expression of two other genes deleted in the patient, CCT6A and SUMF2, for which there is scarce data in the literature. Based on current knowledge and the de novo occurrence of this finding in our proband we presume that the aberration is likely to be pathogenic in our case. However, a single gene disorder, elsewhere in the genome or in this very region cannot be ruled out. Further elucidation of the properties of this chromosomal region, as well as of the role of the genes involved will be needed in order to draw safe conclusions regarding the association of the chromosomal deletion with the patient's features.