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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Induction of PP2A Bp, a regulator of IL-2 deprivation-induced T-cell apoptosis, is deficient in systemic lupus erythematosus
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Induction of PP2A Bp, a regulator of IL-2 deprivation-induced T-cell apoptosis, is deficient in systemic lupus erythematosus

机译：PP2A Bp（IL-2剥夺诱导的T细胞凋亡的调节剂）的诱导缺乏系统性红斑狼疮

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摘要

The activity and substrate specificity of the ubiquitously expressed phosphatase PP2A is determined by the type of regulatory (B) subunit that couples to the catalytic/scaffold core of the enzyme. We determined that the Bp subunit (PPP2R2B) is expressed in resting T cells, its transcription is down-regulated during T-cell activation, and up-regulated in conditions of low IL-2. Specifically, high levels of PP2A Bp were produced during IL-2 deprivation-induced apoptosis, whereas Fas ligation had no effect. Forced expression of the Bp subunit in primary human T cells was sufficient to induce apoptosis, whereas silencing using siRNA protected activated T cells from IL-2 withdrawal-induced cell death. Because T-cell apoptosis is known to be altered in T cells from patients with systemic lupus erythematosus, we analyzed the regulation of PP2A Bp in this autoimmune disease. We found that levels of PP2A Bp did not increase upon IL-2 deprivation in 50% of the patients. Remarkably, this defect was accompanied by resistance to apoptosis. Importantly, kinetics of cell death were normal in cells of patients that up-regulated PP2A Bp in a normal-manner. We have identified a unique role for the phosphatase PP2A, particularly the holoen-zyme formed by PP2A Bp. Bp appears to trigger apoptosis of T cells in the absence of IL-2 and probably contributes to the termination of a no-longer-needed immune response. We propose that defective production of PP2A Bp upon IL-2 deprivation results in apoptosis resistance and longer survival of autoreactive T cells, in a subset of SLE patients.
机译：普遍表达的磷酸酶PP2A的活性和底物特异性取决于与该酶的催化/支架核心偶联的调节（B）亚基的类型。我们确定Bp亚基（PPP2R2B）在静止的T细胞中表达，其转录在T细胞活化过程中被下调，在低IL-2的条件下被上调。具体而言，在IL-2剥夺诱导的细胞凋亡期间会产生高水平的PP2A Bp，而Fas连接则没有作用。 Bp亚基在原代人T细胞中的强制表达足以诱导细胞凋亡，而使用siRNA沉默可保护活化的T细胞免受IL-2戒断诱导的细胞死亡。由于已知系统性红斑狼疮患者的T细胞中T细胞凋亡发生了变化，因此我们分析了PP2A Bp在这种自身免疫性疾病中的调节作用。我们发现在50％的患者中，IL-2剥夺后PP2A Bp的水平并未增加。明显地，该缺陷伴有对凋亡的抗性。重要的是，以正常方式上调PP2A Bp的患者细胞的细胞死亡动力学是正常的。我们已经确定了磷酸酶PP2A的独特作用，尤其是PP2A Bp形成的全酶。在没有IL-2的情况下，Bp似乎会触发T细胞的凋亡，并且可能有助于终止不再需要的免疫应答。我们提出，在部分SLE患者中，IL-2剥夺后PP2A Bp的产生缺陷会导致细胞凋亡抗性和自身反应性T细胞更长的生存期。

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    Jose C. Crispin; Sokratis A. Apostolidis; Melissa I. Finnell; George C. Tsokos;

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    Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215;

    Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215;

    Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215;

    Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215;

  • 收录信息 美国《科学引文索引》(SCI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
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