Protein arginine methyltransferase 5 promotes cholesterol biosynthesis mediated Th17 responses and autoimmunity
Protein arginine methyltransferase 5 promotes cholesterol biosynthesis mediated Th17 responses and autoimmunity
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DOI：
10.1172/jcl131254
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发表时间：
2020-04-01
影响因子：
15.9
通讯作者：
Guerau-de-Arellano, Mireia
中科院分区：
文献类型：
--
作者：
Webb, Lindsay M.;Sengupta, Shouvonik;Guerau-de-Arellano, Mireia
蛋白精氨酸甲基转移酶5 （PRMT5）催化精氨酸的对称二甲基化（SDM），这是一种涉及肿瘤发生和胚胎发育的翻译后修饰。然而，PRMTS调节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PRMTS促进SREBP1 SDM，并诱导胆固醇生物合成通路酶产生类视黄酮相关孤儿受体（ROR）激动剂，激活ROR γ t。CD4+ Th细胞室中PRMTS的特异性缺失抑制Th17分化，并保护小鼠免受实验性自身免疫性脑脊髓炎（EAE）的影响。我们还发现PRMTS在CD4(+) Th细胞生命周期和不变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，PRMTS在最近激活的T细胞中的表达是胆固醇生物合成代谢基因表达程序所必需的，该程序产生RORyt激动活性并促进Th17分化和EAE。这些结果表明，thprmt5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。
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 PRMTS modulates Th cell polarization and autoimmune disease have not yet been elucidated. Here, we found that PRMTS promoted SREBP1 SDM and the induction of cholesterol biosynthetic pathway enzymes that produce retinoid-related orphan receptor (ROR) agonists that activate ROR gamma t. Specific loss of PRMTS in the CD4+ Th cell compartment suppressed Th17 differentiation and protected mice from developing experimental autoimmune encephalomyelitis (EAE). We also found that PRMTS 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 PRMTS expression in recently activated T cells is necessary for the cholesterol biosynthesis metabolic gene expression program that generates RORyt 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.