Protein Phosphatase 2A Enables Expression of Interleukin 17 (IL-17) through Chromatin Remodeling
Protein Phosphatase 2A Enables Expression of Interleukin 17 (IL-17) through Chromatin Remodeling
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DOI：
10.1074/jbc.m113.483743
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发表时间：
2013-09-13
影响因子：
4.8
通讯作者：
Crispin, Jose C.
中科院分区：
文献类型：
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作者：
Apostolidis, Sokratis A.;Rauen, Thomas;Crispin, Jose C.
蛋白磷酸酶2A （PP2A）是一种参与基本细胞功能的异三聚丝氨酸/苏氨酸磷酸酶。系统性红斑狼疮（SLE）患者的T细胞表达高水平的PP2A催化亚基（PP2Ac）。在T细胞中过表达PP2Ac的小鼠以il -17依赖的方式发生肾小球肾炎。在这里，通过微阵列分析，我们证明了PP2Ac表达的增加赋予T细胞产生一系列促炎效应分子的能力。由于IL-17在肾小球肾炎的表达中很重要，我们研究了PP2Ac失调促进其产生的机制。我们报道，PP2Ac通过激活干扰素调节因子4的机制，通过增强组蛋白3乙酰化参与Il17位点的调节。在PP2Ac转基因小鼠和SLE患者的T细胞中，Il17位点的组蛋白3乙酰化升高是共同的。我们提出，通过促进T细胞的炎症能力，PP2Ac失调有助于SLE的发病机制。
Protein phosphatase 2A (PP2A) is a heterotrimeric serine/threonine phosphatase involved in essential cellular functions. T cells from patients with systemic lupus erythematosus (SLE) express high levels of the catalytic subunit of PP2A (PP2Ac). A mouse overexpressing PP2Ac in T cells develops glomerulonephritis in an IL-17-dependent manner. Here, using microarray analyses, we demonstrate that increased expression of PP2Ac grants T cells the capacity to produce an array of proinflammatory effector molecules. Because IL-17 is important in the expression of glomerulonephritis, we studied the mechanism through which PP2Ac dysregulation facilitates its production. We report that PP2Ac is involved in the regulation of the Il17 locus by enhancing histone 3 acetylation through a mechanism that involves activation of interferon regulatory factor 4. Increased histone 3 acetylation of the Il17 locus is shared between T cells of PP2Ac transgenic mice and patients with SLE. We propose that, by promoting the inflammatory capacity of T cells, PP2Ac dysregulation contributes to the pathogenesis of SLE.