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Protein arginine methyltransferase 5 promotes cholesterol biosynthesis mediated Th17 responses and autoimmunity [Th17]

ABSTRACT: Protein Arginine Methyltransferase (PRMT) 5 catalyzes symmetric dimethylation of arginine, a post-translational modification involved in cancer and embryonic development. However, the role and mechanisms by which PRMT5 modulates T helper (Th) cell polarization and autoimmune disease have not yet been elucidated. Here we find that PRMT5 promotes expression of cholesterol biosynthetic pathway enzymes that produce ROR agonists and activate ROR-t, driving Th17 differentiation. Specific loss of PRMT5 in the CD4 Th cell compartment completely protected mice from EAE. We also find that PRMT5 controls thymic and peripheral homeostasis in the CD4 Th cell life cycle, as well as iNK T and CD8 T cell development or maintenance, respectively. This work conclusively demonstrates that PRMT5 expression in recently activated T cells is necessary for expression of a cholesterol biosynthesis metabolic gene expression program that generates ROR-t agonistic activity and promotes Th17 differentiation and EAE. These results point to Th PRMT5 and its downstream cholesterol biosynthesis pathway as promising therapeutic targets in Th17-mediated diseases.

ORGANISM(S): Mus musculus

PROVIDER: GSE141194 | GEO | 2020/02/27

REPOSITORIES: GEO

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Protein arginine methyltransferase 5 promotes cholesterol biosynthesis mediated Th17 responses and autoimmunity [CD4 T-cells]

Project description:Protein Arginine Methyltransferase (PRMT) 5 catalyzes symmetric dimethylation of arginine, a post-translational modification involved in cancer and embryonic development. However, the role and mechanisms by which PRMT5 modulates T helper (Th) cell polarization and autoimmune disease have not yet been elucidated. Here we find that PRMT5 promotes expression of cholesterol biosynthetic pathway enzymes that produce ROR agonists and activate ROR-t, driving Th17 differentiation. Specific loss of PRMT5 in the CD4 Th cell compartment completely protected mice from EAE. We also find that PRMT5 controls thymic and peripheral homeostasis in the CD4 Th cell life cycle, as well as iNK T and CD8 T cell development or maintenance, respectively. This work conclusively demonstrates that PRMT5 expression in recently activated T cells is necessary for expression of a cholesterol biosynthesis metabolic gene expression program that generates ROR-t agonistic activity and promotes Th17 differentiation and EAE. These results point to Th PRMT5 and its downstream cholesterol biosynthesis pathway as promising therapeutic targets in Th17-mediated diseases.

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Regulation of gene expression by RORgamma in Th17 cells

Project description:We observed significant growth inhibition of melanoma tumor in ROR?-/- mice, suggesting an important role for the T helper 17 cell (TH17) pathway in tumor immunity. Though RORgamma t (ROR?t) plays a critical role in the development of IL-17-secreting Th17 cells, the role of other genes remained an open question. To explore the expression of unknown genes with anti-tumor properties, gene expression analysis was performed. Sorted naïve TH cells (CD4+CD25-CD62Lhigh) from RORc+/+ and RORc-/-mice were differentiated under TH17 polarizing conditions. After 4 days, cells were harvested, RNA was isolated and gene expression analysis was performed.

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PRMT5 promotes symmetric dimethylation of RNA processing proteins and modulates activated T cell alternative splicing and Ca2+/NFAT signaling

Project description:Protein Arginine Methyltransferase (PRMT) 5 is the major type 2 methyltransferase catalyzing symmetric dimethylation (SDM) of arginine. PRMT5 inhibition or deletion in CD4 Th cells reduces TcR engagement-induced IL-2 production and Th cell expansion and confers protection against experimental autoimmune encephalomyelitis (EAE), the animal model of Multiple Sclerosis. However, the mechanisms by which PRMT5 modulates T helper (Th) cell proliferation are still not completely understood and neither are the methylation targets in T cells. In this manuscript, we uncover the role of PRMT5 on alternative splicing (AS) in activated T cells and identify several targets of PRMT5 SDM involved in splicing. In addition, we find a possible link between PRMT5 mediated AS of Trpm4 (Transient Receptor Potential Cation Channel Subfamily M Member 4) and TcR/NFAT signaling/IL-2 production. This understanding may guide development of drugs targeting these processes to benefit patients with T cell-mediated diseases.

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Protein arginine methyltransferase 5 promotes cholesterol biosynthesis mediated Th17 responses and autoimmunity [Th17]

Project description:Protein arginine methyltransferase 5 promotes cholesterol biosynthesis mediated Th17 responses and autoimmunity [Th17]

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Protein arginine methyltransferase 5 promotes cholesterol biosynthesis mediated Th17 responses and autoimmunity [CD4 T-cells]

Project description:Protein arginine methyltransferase 5 promotes cholesterol biosynthesis mediated Th17 responses and autoimmunity [CD4 T-cells]

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The AP-1 Transcription Factor JunB Is Required for Th17 Cell Differentiation

Project description:Interleukin (IL)-17-producing T helper (Th17) cells are crucial for host defense against extracellular microbes and pathogenesis of autoimmune diseases. Here we show that the AP-1 transcription factor JunB is required for Th17 cell development. Junb-deficient CD4+ T cells are able to develop in vitro into various helper T subsets except Th17. The RNA-seq transcriptome analysis reveals that JunB is crucial for the Th17-specific gene expression program. Junb-deficient mice are completely resistant to experimental autoimmune encephalomyelitis, a Th17-mediated inflammatory disease, and naive T helper cells from such mice fail to differentiate into Th17 cells. JunB appears to activate Th17 signature genes by forming a heterodimer with BATF, another AP-1 factor essential for Th17 differentiation. The mechanism whereby JunB controls Th17 cell development likely involves activation of the genes for the Th17 lineage-specifying orphan receptors RORt and ROR and reduced expression of Foxp3, a transcription factor known to antagonize RORt function.

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Chemical Inhibition of the ROR?t-dependent Transcriptional Network in Th17 cells [RNA-Seq]

Project description:ROR?t is a transcription factor required for T helper 17 (Th17) cell development. We identified three ROR?t-specific inhibitors that suppress Th17 cell responses including Th17 cell-mediated autoimmune disease. We systemically characterized ROR?t binding data in the presence and absence of drug with corresponding whole-transcriptome sequencing for wild-type and ROR?t-deficient cells. ROR?t is central in a densely interconnected regulatory network, acting both as a direct activator of genes important for Th17 cell differentiation and as a direct repressor of genes from other T-cell lineages. The three inhibitors identified here reversed both of these modes of action, but to varying extents and through distinct mechanisms. Whereas one inhibitor displaced ROR?t from its target-loci, the two more potent inhibitors affected transcription predominantly without removing DNA-binding. Our work illustrates the power of a system-scale analysis of transcriptional regulation to characterize potential therapeutic compounds that inhibit pathogenic Th17 cells and suppress autoimmunity. Transcriptional profiling of Th17 cells under chemical perturbations of ROR?t, DMSO, and knockout of ROR?t

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Protein arginine methyltransferase 5 promotes cholesterol biosynthesis mediated Th17 responses and autoimmunity

Project description:Protein arginine methyltransferase 5 promotes cholesterol biosynthesis mediated Th17 responses and autoimmunity

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Project description:RORgt is known to instruct the differentiation of Th17 cells that mediate the pathogenesis of autoimmune diseases. However, it remains unknown whether RORgt plays a distinct role in the differentiation and effector function of Th17 cells. Here we show that mutation of RORgt lysine 256, a ubiquitination site, to arginine (K256R) separates the RORgt role in these two functions. Preventing ubiquitination at K256 via arginine substitution does not affect RORgt-dependent thymocyte development and Th17 differentiation in vitro and in vivo, however, greatly impaired the pathogenesis of Th17 cell-mediated experimental autoimmune encephalomyelitis (EAE). Mechanistically, K256R mutation impairs RORgt to bind to and activate Runx1 expression critical for Th17-mediated EAE. Thus, RORgt regulates the effector function of Th17 cells in addition to Th17 differentiation. This work informs the development of RORgt-based therapies that specifically target the effector function of Th17 cells responsible for autoimmunity.

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