T cell maturation, selection, and function differentially depend on the chaperonin CCT
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ABSTRACT:
PROVIDER: PRJNA613424 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR11349918_1.fastq.gz | Fastqsanger.gz | |||
| SRR11349918_2.fastq.gz | Fastqsanger.gz | |||
| SRR11349919_1.fastq.gz | Fastqsanger.gz | |||
| SRR11349919_2.fastq.gz | Fastqsanger.gz | |||
| SRR11349920_1.fastq.gz | Fastqsanger.gz |
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Project description:T cell homeostasis rely on de-novo transcription of proteins to ensure antigen-specific immunity. Central in this process and to ensure efficient and correct protein folding and turn-over is the Eukaryotic Type II chaperons, which primary targets are actin and tubulin. So far its role in T cell development and function remain unclear. Using a conditional deletion of a subunit within the type II chaperon complex we show this complex to be indispensable for correct maturation of thymocytes, with a reduced thymic output of mature effector and regulatory T cells. Accordingly, we found the formation of nuclear actin filaments to be reduced resulting in an array of functional effects with the most prominent being the failure to commit to the Th2 cell linage with a further insufficiency in recruiting cellular and humoral effector mechanisms to command an effective anti-parasitic response. Hence, our results highlight the importance of the Eukaryotic Type II chaperons in shaping the fate and function of CD4 T cells.
2021-06-07 | GSE147209 | GEO
Project description:The eukaryotic cytoplasmic chaperonin-containing TCP-1 (CCT) is a complex formed by two back-to-back stacked hetero-octameric rings that assists the folding of actins, tubulins and other proteins in an ATP-dependent manner. Here, we decided to test the significance of the hetero-oligomeric nature of CCT for its function by introducing, in each of the eight subunits in turn, an identical mutation at a position involved in ATP binding and conserved in all the subunits, in order to establish the extent of ‘individuality’ of the various subunits. Our results show that these identical mutations lead to dramatically different phenotypes. For example, cells with the mutation in CCT2 have an excess of actin patches and are the only pseudo-diploid strain. By contrast, cells with the mutation in CCT7 are the only ones to accumulate juxta-nuclear protein aggregates that may reflect the absence of stress response in this strain. System-level analysis of the strains using RNA microarrays reveals connections between CCT and several cellular networks including ribosome biogenesis and TOR2 that help to explain the phenotypic variability observed We used microarrays to reveal the differences in mRNA expression caused by the different mutations.
2010-07-01 | GSE19511 | GEO
Project description:The eukaryotic cytoplasmic chaperonin-containing TCP-1 (CCT) is a complex formed by two back-to-back stacked hetero-octameric rings that assists the folding of actins, tubulins and other proteins in an ATP-dependent manner. Here, we decided to test the significance of the hetero-oligomeric nature of CCT for its function by introducing, in each of the eight subunits in turn, an identical mutation at a position involved in ATP binding and conserved in all the subunits, in order to establish the extent of ‘individuality’ of the various subunits. Our results show that these identical mutations lead to dramatically different phenotypes. For example, cells with the mutation in CCT2 have an excess of actin patches and are the only pseudo-diploid strain. By contrast, cells with the mutation in CCT7 are the only ones to accumulate juxta-nuclear protein aggregates that may reflect the absence of stress response in this strain. System-level analysis of the strains using RNA microarrays reveals connections between CCT and several cellular networks including ribosome biogenesis and TOR2 that help to explain the phenotypic variability observed We used microarrays to reveal the differences in mRNA expression caused by the different mutations. All yeast strains were grown at 30 °C to OD(600)=0.5. Their total RNA was extracted and reverse transcribed to cDNA and transcribed back to RNA in the presence of biotinylated nucleotide analog. The biotinylated RNA was fragmented and hybridized to GenCHip Yeast Genome 2.0 array.
2010-06-30 | E-GEOD-19511 | biostudies-arrayexpress
Project description:Chemical cross-linking coupled to mass spectrometry was used to study assembly intermediates of the chaperonin TRiC/CCT. Complex were cross-linked with the homobifunctional, noncleavable reagent, disuccinimidyl suberate (DSS).
2023-08-24 | PXD043532 | Pride
Project description:When the chaperonin complex CCT is partially silenced in Jurkat-derived T cell line J77 E61, we observe changes in the production of exosomes and in their composition. Thus, to explore the bases of these alterations and find possible new mechanisms of exosome biosynthesis regulation we characterized the lipidome content in cells where the chaperonin complex CCT was partially silent (CCT) and controls (CTRL). We analyzed 5 biological replicates containing 3 × 106 cells using LC-MS in positive and negative polarity mode. For quality control, 5 QCs samples and 4 blanks were also included in the analysis (total 19 samples and 2 groups).
2022-06-03 | ST002185 | MetabolomicsWorkbench
Project description:Chemical cross-linking coupled to mass spectrometry was used to study the folding of the client protein, beta-tubulin, by the chaperonin TRiC/CCT. Different complexes containing TRiC/CCT and/or the chaperone prefoldin were cross-linked in absence or presence of nucleotides with the homobifunctional, noncleavable reagent, disuccinimidyl suberate (DSS).
2022-12-08 | PXD030590 | Pride
Project description:Folding newly synthesized proteins relies on the ribosome intricately coordinating mRNA translation with a network of ribosome-associated machinery. The principles that drive the coordination of this diverse machinery remain poorly understood. Here, we use selective ribosome profiling to determine how the essential chaperonin TRiC/CCT and the Hsp70 Ssb are recruited to ribosome-nascent chain complexes to mediate cotranslational protein folding. Whereas substrate localization and nascent chain sequence are the major determinants of cotranslational recruitment of Ssb, we found that temporal and structural elements drive TRiC engagement. For both chaperones, however, local slowdowns in translation enhance chaperone enrichment. This work helps define the principles that dictate the coordinated activity of ribosome-associated factors to perform their critical role in maintaining a properly folded nascent proteome.
2019-08-22 | GSE114882 | GEO
Project description:The APOBEC3 cytosine deaminases are implicated as the cause of a prevalent somatic mutation pattern found in cancer genomes. The APOBEC3 enzymes act as viral restriction factors by mutating viral genomes. Mutation of the cellular genome is presumed to be an off-target activity of the enzymes, although the regulatory measures for APOBEC3 expression and activity remain undefined. It is therefore difficult to predict the circumstances that enable APOBEC3 interaction with cellular DNA that leads to mutagenesis. The APOBEC3A (A3A) enzyme is the most potent deaminase of the family. Using proteomics, we evaluated protein interactors of A3A to identify potential regulators. We found that A3A interacts with the Chaperonin Containing TCP-1 (CCT) complex, a cellular machine that assists in protein folding and function. Importantly, depletion of CCT resulted in increased A3A-induced cytotoxicity. Evaluation of cancer genomes demonstrated an enrichment of A3A mutational signatures in cancers with silencing mutations in CCT subunit genes. Together, these data suggest that the CCT complex interacts with A3A, and that disruption of CCT function results in increased A3A mutational activity.
2021-07-02 | PXD024191 | Pride
Project description:Please provide an overall description of your study, think something similar in scope to the manuscript abstractCell proteostasiCell proteostasis includes gene transcription, protein translation, folding of de novo proteins, post-translational modification, secretion, degradation and recycling. By profiling the proteome of extracellular vesicles (EVs) from T cells, we have found the chaperonin complex CCT, involved in the correct folding of particular proteins. By limiting CCT cell-content by siRNA, cells undergo altered lipid composition and metabolic rewiring towards a lipid-dependent metabolism, with increased activity of peroxisomes and mitochondria. This is due to dysregulation of the dynamics of interorganellar contacts between lipid droplets, mitochondria, peroxisomes and the endolysosomal system. This process accelerates the biogenesis of multivesicular bodies leading to higher EV production through the dynamic regulation of microtubule-based kinesin motors. These findings connect proteostasis with lipid metabolism through an unexpected role of CCT.s includes gene transcription, protein translation, folding of de novo proteins, post-translational modification, secretion, degradation and recycling. By profiling the proteome of extracellular vesicles (EVs) from T cells, we have found the chaperonin complex CCT, involved in the correct folding of particular proteins. By limiting CCT cell-content by siRNA, cells undergo altered lipid composition and metabolic rewiring towards a lipid-dependent metabolism, with increased activity of peroxisomes and mitochondria. This is due to dysregulation of the dynamics of interorganellar contacts between lipid droplets, mitochondria, peroxisomes and the endolysosomal system. This process accelerates the biogenesis of multivesicular bodies leading to higher EV production through the dynamic regulation of microtubule-based kinesin motors. These findings connect proteostasis with lipid metabolism through an unexpected role of CCT.
2023-07-20 | PXD034917 | Pride
Project description: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. Here we demonstrate that the eukaryotic type II chaperonin complex CCT is indispensable for T cell development, function, stress-response, and metabolism. CCT-deficient thymoyctes are compromised in their selection, differentiation, and late stage maturation. The lack of CCT expression prevents a normal response to T cell activation induced changes in the proteome, stops the formation of nuclear actin filaments and impairs a normal cells stress response. Consequently, T cell homeostatic maintenance and receptor-mediated stimulation of proliferation are impaired in CCT-deficient T cells leading to activation-induced cell death. Furthermore, Th2 polarization digresses in the absence of CCT-controlled protein folding leading paradoxically to continued IFN-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. Taken together, these findings demonstrate that both normal thymopoiesis and peripheral T cell biology are critically dependent on CCT-controlled proteostasis and that its absence is incompatible with protective immunity.
2021-09-09 | PXD018834 | Pride