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Project description:Protein arginine methyltransferase 5 (PRMT5) catalyzes symmetric dimethylation (SDM) of arginine, a posttranslational modification involved in oncogenesis and embryonic development. However, the role and mechanisms by which PRMT5 modulates Th cell polarization and autoimmune disease have not yet been elucidated. Here, we found that PRMT5 promoted SREBP1 SDM and the induction of cholesterol biosynthetic pathway enzymes that produce retinoid-related orphan receptor (ROR) agonists that activate RORγt. Specific loss of PRMT5 in the CD4+ Th cell compartment suppressed Th17 differentiation and protected mice from developing experimental autoimmune encephalomyelitis (EAE). We also found that PRMT5 controlled thymic and peripheral homeostasis in the CD4+ Th cell life cycle and invariant NK (iNK) T cell development and CD8+ T cell maintenance. This work demonstrates that PRMT5 expression in recently activated T cells is necessary for the cholesterol biosynthesis metabolic gene expression program that generates RORγt 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.
| S-EPMC7108896 | biostudies-literature
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.
2020-02-27 | GSE141194 | GEO
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.
2020-02-27 | GSE141168 | GEO
Project description:Protein arginine methyltransferase 5 promotes cholesterol biosynthesis mediated Th17 responses and autoimmunity [Th17]
| PRJNA592563 | ENA
Project description:Protein arginine methyltransferase 5 promotes cholesterol biosynthesis mediated Th17 responses and autoimmunity
| PRJNA592557 | ENA
Project description:Protein arginine methyltransferase 5 promotes cholesterol biosynthesis mediated Th17 responses and autoimmunity [CD4 T-cells]
| PRJNA592541 | ENA
Project description:Protein arginine methylation regulates diverse functions of eukaryotic cells, including gene expression, the DNA damage response, and circadian rhythms. We showed that arginine residues within the third intracellular loop of the human D2 dopamine receptor, which are conserved in the DOP-3 receptor in the nematode Caenorhabditis elegans, were methylated by protein arginine methyltransferase 5 (PRMT5). By mutating these arginine residues, we further showed that their methylation enhanced the D2 receptor-mediated inhibition of cyclic adenosine monophosphate (cAMP) signaling in cultured human embryonic kidney (HEK) 293T cells. Analysis of prmt-5-deficient worms indicated that methylation promoted the dopamine-mediated modulation of chemosensory and locomotory behaviors in C. elegans through the DOP-3 receptor. In addition to delineating a previously uncharacterized means of regulating GPCR (heterotrimeric guanine nucleotide-binding protein-coupled receptor) signaling, these findings may lead to the development of a new class of pharmacological therapies that modulate GPCR signaling by changing the methylation status of these key proteins.
| S-EPMC5473623 | biostudies-literature
Project description:SHARPIN, an adaptor for the linear ubiquitin chain assembly complex (LUBAC), plays important roles in NF-?B signaling and inflammation. Here, we have demonstrated a LUBAC-independent role for SHARPIN in regulating melanoma growth. We observed that SHARPIN interacted with PRMT5, a type II protein arginine methyltransferase, and increased its multiprotein complex and methyltransferase activity. Activated PRMT5 controlled the expression of the transcription factors SOX10 and MITF by SHARPIN-dependent arginine dimethylation and inhibition of the transcriptional corepressor SKI. Activation of PRMT5 by SHARPIN counteracted PRMT5 inhibition by methylthioadenosine, a substrate of methylthioadenosine phosphorylase, which is codeleted with cyclin-dependent kinase inhibitor 2A (CDKN2A) in approximately 15% of human cancers. Collectively, we identified a LUBAC-independent role for SHARPIN in enhancing PRMT5 activity that contributes to melanomagenesis through the SKI/SOX10 regulatory axis.
| S-EPMC5749505 | biostudies-literature
Project description:Ca2+ release-activated Ca2+ channel regulator 2A (CRACR2A) is expressed abundantly in T cells and acts as a signal transmitter between TCR stimulation and activation of the Ca2+/NFAT and JNK/AP1 pathways. CRACR2A has been linked to human diseases in numerous genome-wide association studies and was shown to be one of the most sensitive targets of the widely used statin drugs. However, the physiological role of CRACR2A in T cell functions remains unknown. In this study, using transgenic mice for tissue-specific deletion, we show that CRACR2A promotes Th1 responses and effector function of Th17 cells. CRACR2A was abundantly expressed in Th1 and Th17 cells. In vitro, deficiency of CRACR2A decreased Th1 differentiation under nonpolarizing conditions, whereas the presence of polarizing cytokines compensated this defect. Transcript analysis showed that weakened TCR signaling by deficiency of CRACR2A failed to promote Th1 transcriptional program. In vivo, conditional deletion of CRACR2A in T cells alleviated Th1 responses to acute lymphocytic choriomeningitis virus infection and imparted resistance to experimental autoimmune encephalomyelitis. Analysis of CNS from experimental autoimmune encephalomyelitis-induced mice showed impaired effector functions of both Th1 and Th17 cell types, which correlated with decreased pathogenicity. Collectively, our findings demonstrate the requirement of CRACR2A-mediated TCR signaling in Th1 responses as well as pathogenic conversion of Th17 cells, which occurs at the site of inflammation.
| S-EPMC6081249 | biostudies-literature
Project description:In the family of protein arginine methyltransferases (PRMTs) that predominantly generate either asymmetric or symmetric dimethylarginine (SDMA), PRMT7 is unique in producing solely monomethylarginine (MMA) products. The type of methylation on histones and other proteins dictates changes in gene expression, and numerous studies have linked altered profiles of methyl marks with disease phenotypes. Given the importance of specific inhibitor development, it is crucial to understand the mechanisms by which PRMT product specificity is conferred. We have focused our attention on active-site residues of PRMT7 from the protozoan Trypanosoma brucei We have designed 26 single and double mutations in the active site, including residues in the Glu-Xaa8-Glu (double E) loop and the Met-Gln-Trp sequence of the canonical Thr-His-Trp (THW) loop known to interact with the methyl-accepting substrate arginine. Analysis of the reaction products by high resolution cation exchange chromatography combined with the knowledge of PRMT crystal structures suggests a model where the size of two distinct subregions in the active site determines PRMT7 product specificity. A dual mutation of Glu-181 to Asp in the double E loop and Gln-329 to Ala in the canonical THW loop enables the enzyme to produce SDMA. Consistent with our model, the mutation of Cys-431 to His in the THW loop of human PRMT9 shifts its product specificity from SDMA toward MMA. Together with previous results, these findings provide a structural basis and a general model for product specificity in PRMTs, which will be useful for the rational design of specific PRMT inhibitors.
| S-EPMC5000077 | biostudies-literature