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.

中文翻译：

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蛋白质精氨酸甲基转移酶 5 促进胆固醇生物合成介导的 Th17 反应和自身免疫。

蛋白质精氨酸甲基转移酶 5 (PRMT5) 催化精氨酸的对称二甲基化 (SDM)，这是一种参与肿瘤发生和胚胎发育的翻译后修饰。然而，PRMT5 调节 Th 细胞极化和自身免疫性疾病的作用和机制尚未阐明。在这里，我们发现 PRMT5 促进 SREBP1 SDM 和胆固醇生物合成途径酶的诱导，这些酶产生激活 RORγt 的视黄醇相关孤儿受体 (ROR) 激动剂。CD4+ Th 细胞区室中 PRMT5 的特异性缺失抑制了 Th17 分化，并保护小鼠免于发展为实验性自身免疫性脑脊髓炎 (EAE)。我们还发现 PRMT5 在 CD4+ Th 细胞生命周期以及不变 NK (iNK) T 细胞发育和 CD8+ T 细胞维持中控制胸腺和外周稳态。这项工作表明，最近激活的 T 细胞中 PRMT5 的表达对于胆固醇生物合成代谢基因表达程序是必需的，该程序产生 RORγt 激动活性并促进 Th17 分化和 EAE。这些结果表明 Th PRMT5 及其下游胆固醇生物合成途径是 Th17 介导疾病的有希望的治疗靶点。