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首页> 外文期刊>Arteriosclerosis, thrombosis, and vascular biology >Phosphorylation of protein inhibitor of activated STAT1 (PIAS1) by MAPK-activated protein kinase-2 inhibits endothelial inflammation via increasing both PIAS1 transrepression and SUMO E3 ligase activity
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Phosphorylation of protein inhibitor of activated STAT1 (PIAS1) by MAPK-activated protein kinase-2 inhibits endothelial inflammation via increasing both PIAS1 transrepression and SUMO E3 ligase activity

机译：MAPK激活的蛋白激酶2对激活的STAT1（PIAS1）蛋白抑制剂的磷酸化通过增加PIAS1反式抑制和SUMO E3连接酶的活性来抑制内皮炎症

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Objective-: Protein inhibitor of activated signal transducer and activator of transcription-1 (PIAS1) is known to function as small ubiquitin-like modifier (SUMO) E3 ligase as well as transrepressor. The aim of the study is to elucidate the regulatory mechanisms for these 2 different functions, especially with respect to endothelial inflammation. METHODS AND RESULTS-: The mitogen-activated protein kinase (MAPK)-activated protein kinase-2 is a proinflammatory kinase and phosphorylates PIAS1 at the Ser522 residue. Activation of MAPK-activated protein kinase-2 enhances p53-SUMOylation, but a PIAS1 phosphorylation mutant, PIAS1-S522A, abolished this p53-SUMOylation, suggesting a critical role for PIAS1-S522 phosphorylation in its SUMO ligase activity. Because nuclear p53 can inhibit Kruppel-like factor 2 promoter activity, we investigated the roles for PIAS1 phosphorylation and p53-SUMOylation in the Kruppel-like factor 2 and endothelial NO synthase expression. Both MAPK-activated protein kinase-2 and PIAS1 overexpression increased Kruppel-like factor 2 promoter activity and endothelial NO synthase expression, which were inhibited by expressing a p53-SUMOylation defective mutant, p53-K386R, and PIAS1-S522A. PIAS1-S522A also abolished the anti-inflammatory effect of wild-type PIAS1 in vitro and also in vivo, which was examined by leukocyte rolling in microvessels of skin grafts transduced by adenovirus encoding PIAS1-WT or-S522A mutant. CONCLUSION-: Our study has identified a novel negative feedback regulatory pathway through which MAPK-activated protein kinase-2 limits endothelial inflammation via the PIAS1 S522 phosphorylation-mediated increase in PIAS1 transrepression and SUMO ligase activity.
机译：目的-：已知激活信号转导子的蛋白抑制剂和转录激活因子1（PIAS1）既可作为小型泛素样修饰剂（SUMO）E3连接酶，又可作为反转录抑制子。该研究的目的是阐明这两种不同功能的调节机制，尤其是在内皮炎症方面。方法和结果：丝裂原活化蛋白激酶（MAPK）活化蛋白激酶2是一种促炎性激酶，在Ser522残基处磷酸化PIAS1。 MAPK激活的蛋白激酶2的激活增强了p53-SUMO酰化，但是PIAS1磷酸化突变体PIAS1-S522A取消了该p53-SUMO酰化，表明PIAS1-S522磷酸化在其SUMO连接酶活性中起着关键作用。因为核p53可以抑制Kruppel样因子2启动子活性，所以我们研究了PIAS1磷酸化和p53-SUMOylation在Kruppel样因子2和内皮细胞NO合酶表达中的作用。 MAPK激活的蛋白激酶2和PIAS1的过表达均增加了Kruppel样因子2启动子活性和内皮一氧化氮合酶的表达，这被表达p53-SUMOylation缺陷型突变体p53-K386R和PIAS1-S522A抑制。 PIAS1-S522A还消除了野生型PIAS1在体内和体外的抗炎作用，通过在编码PIAS1-WT或-S522A突变体的腺病毒转导的皮肤移植物的微血管中白细胞滚动检测了PIAS1-S522A的抗炎作用。结论-：我们的研究已经确定了一种新型的负反馈调节途径，MAPK激活的蛋白激酶2通过PIAS1 S522磷酸化介导的PIAS1反转录和SUMO连接酶活性的增加来限制内皮炎症。

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