Phosphatase PP2A is essential for TH17 differentiation
Phosphatase PP2A is essential for TH17 differentiation
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磷酸酶 PP2A 对于 TH17 分化至关重要
DOI：
10.1073/pnas.1807484116
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发表时间：
2018
期刊：
影响因子：
--
通讯作者：
Lu Linrong
中科院分区：
文献类型：
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作者：
Xu Qin;Jin Xuexiao;Zheng Mingzhu;Rohila Deepak;Fu Guotong;Wen Zhuoyu;Lou Jun;Wu Songquan;Sloan Richard;Wang Lie;Hu Hu;Gao Xiang;Lu Linrong
磷酸酶PP 2A表达水平与系统性红斑狼疮（SLE）的临床严重程度和IL 17 A细胞因子过度产生正相关，表明PP 2A在控制TH 17分化和炎症中的潜在作用。通过产生具有外周成熟T细胞中PP 2A的催化亚基α的消融的小鼠品系（PP 2A cKO），我们证明了PP 2A复合物对于TH 17分化是必需的。这些PP 2A cKO小鼠在实验性自身免疫性脑脊髓炎（EAE）模型中具有减少的TH 17细胞数量和较不严重的疾病。PP 2A缺陷也消融SMAD 2的C-末端磷酸化，但增加SMAD 3的C-末端磷酸化。通过结合调节RORγt的活性，这些R-SMADs磷酸化状态的改变降低了IL 17基因的转录。最后，PP 2A抑制剂对TH 17细胞显示出与在PP 2A cKO小鼠中观察到的相似的作用，即，减少TH 17分化和相对保护小鼠免于EAE。总之，这些数据表明，磷酸酶PP 2A是TH 17分化所必需的，并且PP 2A的抑制可能是控制TH 17驱动的自身免疫性疾病的可能的治疗方法。
Phosphatase PP2A expression levels are 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 ablation of the catalytic subunit α of PP2A in peripheral mature T cells (PP2A cKO), we demonstrate that the PP2A complex is essential for TH17 differentiation. These PP2A cKO mice had reduced TH17 cell numbers and less severe disease in an experimental autoimmune encephalomyelitis (EAE) model. PP2A deficiency also ablated C-terminal phosphorylation of SMAD2 but increased C-terminal phosphorylation of SMAD3. By regulating the activity of RORγt via binding, the changes in the phosphorylation status of these R-SMADs reducedIl17agene transcription. Finally, PP2A inhibitors showed similar effects on TH17 cells as were observed in PP2A cKO mice, i.e., decreased TH17 differentiation and relative protection of mice from EAE. Taken together, these data demonstrate that phosphatase PP2A is essential for TH17 differentiation and that inhibition of PP2A could be a possible therapeutic approach to controlling TH17-driven autoimmune diseases.