PP2A is essential for Th17 differentiaiton
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ABSTRACT:
PROVIDER: PRJNA490432 | ENA |
REPOSITORIES: ENA
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Project description:Phosphatase PP2A expression level is positively correlated to the clinical severity of systemic lupus erythematosus (SLE) and IL17A cytokine overproduction, indicating a potential role of PP2A in controlling TH17 differentiation and inflammation. By generating a mouse strain with the ablation of the catalytic subunit α of PP2A in peripheral mature T cells (PP2A cKO), we provide evidence here that PP2A complex is essential in TH17 differentiation. Hence, PP2A cKO mice exhibited a selective reduction of TH17 cell numbers and an attenuated disease severity in an experimental autoimmune encephalomyelitis (EAE) model. Importantly, PP2A deficiency ablated c-terminal phosphorylation of SMAD2 whereas increased c-terminal phosphorylation of SMAD3. Through direct binding to and regulating the activity of RORγt, the phosphorylational changes of these R-SMADs subsequently reduced Il17a transcription. Finally, PP2A inhibitors recapitulated the phenotype of PP2A cKO mice, i.e., inhibiting TH17 differentiation and protecting mice from EAE. Together, the current study proves that phosphatase PP2A is essential for TH17 differentiation, and inhibition of PP2A could be a possible therapeutic approach for the controlling of TH17-driven autoimmune diseases.
2018-09-13 | GSE119836 | GEO
Project description:Protein phosphatase 2A (PP2A), a serine/threonine phosphatase, has been shown to control T cell function. We found that in vitro activated B cells and B cells from various lupus-prone mice and patients with systemic lupus erythematosus display increased PP2A activity. To understand the contribution of PP2A to B cell function, we generated a Cd19CrePpp2r1aflox/flox (flox/flox) mouse which lacks functional PP2A only in B cells. Flox/flox mice displayed reduced spontaneous germinal center formation and decreased responses to T-dependent and T-independent antigens while their B cells responded poorly in vitro to stimulation with an anti-CD40 antibody or CpG in the presence of IL-4. Transcriptome and metabolome studies revealed altered NAD and purine/pyrimidine metabolism and increased expression of purine nucleoside phosphorylase in PP2A-deficient B cells. Our results demonstrate that PP2A is required for optimal B cell function and may contribute to increased B cell activity in systemic autoimmunity.
2020-02-04 | GSE144700 | GEO
Project description:Cancerous inhibitor of PP2A (CIP2A) Constrains Th17 Differentiation by Modulating STAT3 Signaling
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Project description: Not available
| S-EPMC6338861 | biostudies-literature
Project description:we performed proteome analysis of Th9 cells to understand the involvement of proteins that might be crucial for the anti-tumor functions of Th9 cells. Here we show for the first time a comprehensive proteomic analysis of murine Th0 and Th9 cells, which identified 1451 total proteins among which 1367 proteins were common. Further analysis revealed that 118 proteins were upregulated while 81 proteins were downregulated in Th9 cells. Pathway analysis suggested an abundance of phosphoproteins in the proteome of Th9 cells. Among upregulated phosphoproteins which showed to be involved in immune 34 system, Ppp2ca (catalytic subunit of protein phosphatase, PP2A) was found to be highly expressed in Th9 cells. Although the role of PP2A has been shown to regulate the differentiation and functions of Th1,Th2, Th17 and Tregs, its role in differentiation and functions of Th9 cells is not identified yet. Our results show for the first time that PP2A is required for the differentiation and anti-tumor functions of Th9 cells. PP2A inhibition leads to the suppression of IL-9 induction and the expression of key transcription factors of Th9 cells.
2021-09-09 | PXD019506 | Pride
Project description:Serine/Threonine phosphatase PP2A is essential for optimal B cell function
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Project description:The phosphorylation and dephosphorylation of transcription machinery are essential for the precise control of gene expression. A non-canonical protein phosphatase 2A (PP2A) holoenzyme (denoted INTAC), in which the 14-subunit Integrator recruits RNA polymerase II (Pol II) and the PP2A core enzyme dephosphorylates the C-terminal repeat domain (CTD) of Pol II at Serine-5 and Serine-2.
2020-12-02 | GSE154093 | GEO
Project description:RAS-mediated human cell transformation requires inhibition of the tumor suppressor Protein Phosphatase 2A (PP2A). Both RAS and PP2A mediate their effects by phosphoregulation, but phosphoprotein targets and cellular processes in which RAS and PP2A activities converge in human cancers have not been systematically analyzed. Here, based on mass spectrometry phosphoproteome data we discover that phosphosites co-regulated by RAS and PP2A are enriched on proteins involved in epigenetic gene regulation. As examples, RAS and PP2A co-regulate the same phosphorylation sites on HDAC1/2, KDM1A, MTA1/2, RNF168 and TP53BP1. Mechanistically, we validate co-regulation of NuRD chromatin repressor complex by RAS and PP2A. Consistent with their known synergistic effects in cancer, RAS activation and PP2A inhibition resulted in epigenetic reporter de-repression and activation of oncogenic transcription. Notably, transcriptional de-repression by PP2A inhibition was associated with increased euchromatin and decrease in global DNA methylation. Further, targeting of RAS- and PP2A-regulated epigenetic proteins decreased viability of KRAS-mutant human lung cancer cells. Collectively the results indicate that epigenetic protein complexes involved in oncogenic gene expression constitute a significant point of convergence for RAS hyperactivity and PP2A inhibition in cancer. Further, this work provides a resource for future studies focusing on phosphoregulation as a previously unappreciated layer of regulation of epigenetic gene regulation in cancer, and in other RAS/PP2A-regulated cellular processes.
2023-02-06 | GSE220590 | GEO
Project description:Pyruvate dehydrogenase (PDH) is the central enzyme connecting glycolysis and the tricarboxylic acid (TCA) cycle. The importance of PDH function in Th17 cells is unknown. Here, we show that PDH is essential for the generation of a unique glucose-derived citrate pool needed for Th17 cell proliferation, survival and effector function. In vivo, mice harboring a T cell-specific deletion of PDH were less susceptible to developing experimental autoimmune encephalomyelitis. Mechanistically, the absence of PDH in Th17 cells increased glutaminolysis, glycolysis, and lipid uptake in an mTOR-dependent manner. However, cellular citrate remained critically low in mutant Th17 cells, which interfered with oxidative phosphorylation (OXPHOS), lipid synthesis and histone acetylation crucial for the transcription of Th17 signature genes. Increasing cellular citrate in PDH-deficient Th17 cells restored their metabolism and function, identifying a metabolic feedback loop within central carbon metabolism that may offer possibilities for therapeutically targeting Th17 cell-driven autoimmunity.
2023-03-02 | GSE222878 | GEO
Project description:Memory helper T (Th) cells are crucial for secondary immune responses against infectious microorganisms but also drive the pathogenesis of chronic inflammatory diseases. Therefore, it is of fundamental importance to understand how memory T cells are generated. However, the molecular mechanisms governing memory Th cell generation remain incompletely understood. Here, we identified CD30 as a molecule heterogeneously expressed on effector Th1 and Th17 cells, and CD30hi effector Th1 and Th17 cells preferentially generated memory Th1 and Th17 cells. We found that CD30 mediated signal induced Transglutaminase-2 (TG2) expression, and that the TG2 expression in effector Th cells is essential for memory Th cell generation. In fact, Cd30-deficiency resulted in the impaired generation of memory Th1 and Th17 cells, which can be rescued by overexpression of TG2. Furthermore, transglutaminase-2 (Tgm2)-deficient CD4 T cells failed to become memory Th cells. As a result, T cells from Tgm2-deficient mice displayed impaired antigen-specific antibody production and attenuated Th17-mediated allergic responses. Our data indicate that CD30-induced TG2 expression in effector Th cells is essential for the generation of memory Th1 and Th17 cells, and that CD30 can be a marker for precursors of memory Th1 and Th17 cells.
2020-05-28 | GSE151301 | GEO