From the Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts 02215.
J Biol Chem. 2013 Sep 13;288(37):26775-84. doi: 10.1074/jbc.M113.483743. Epub 2013 Aug 5.
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.
蛋白磷酸酶 2A（PP2A）是一种参与重要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，我们通过微阵列分析表明，PP2Ac 的表达增加赋予 T 细胞产生一系列促炎效应分子的能力。因为 IL-17 在肾小球肾炎的表达中很重要，所以我们研究了通过何种机制，PP2Ac 的失调促进了其产生。我们报告说，PP2Ac 通过通过激活干扰素调节因子 4 来增强组蛋白 3 乙酰化，从而参与 Il17 基因座的调节。PP2Ac 转基因小鼠和 SLE 患者的 T 细胞之间共享 Il17 基因座的组蛋白 3 乙酰化增加。我们提出，通过促进 T 细胞的炎症能力，PP2Ac 的失调有助于 SLE 的发病机制。
