Regulation of the innate immune response by threonine-phosphatase of Eyes absent
Regulation of the innate immune response by threonine-phosphatase of Eyes absent
复制标题
DOI：
10.1038/nature08138
复制
发表时间：
2009-07-23
期刊：
影响因子：
64.8
通讯作者：
Nagata, Shigekazu
中科院分区：
文献类型：
--
作者：
Okabe, Yasutaka;Sano, Teruyuki;Nagata, Shigekazu
先天免疫不仅受到病毒或细菌成分的刺激，还受到非微生物危险信号（损伤相关分子模式）的刺激（1）。与损伤相关的分子模式之一是逃避降解的染色体DNA。在程序性细胞死亡和红细胞生成中，来自死细胞或从成红细胞排出的核的DNA在它们被吞噬后被巨噬细胞中的DNA酶II消化。DNase II-/-（也称为Dnase 2a（-/-））小鼠患有严重贫血或慢性关节炎，这是由于在Toll样受体（TLR）非依赖性机制（4）中携带未消化DNA（2，3）的巨噬细胞产生干扰素-β（IFN-β）和肿瘤坏死因子-α（TNF-α）所致。在这里，我们发现Eyes absence 4（EYA 4），最初被鉴定为一种共转录因子，刺激IFN-β和CXCL 10的表达，以响应凋亡细胞的未消化DNA。EYA 4增强了针对病毒（纽卡斯尔病病毒和水泡性口炎病毒）的先天免疫应答，并且可以与信号分子（IPS-1（也称为MAVS）、STING（TMEM 173）和NLRX 1）缔合。三个研究小组先前已证明EYA具有磷酸酶活性（5-7）。我们发现，小鼠EYA家族成员作为磷酸酪氨酸和磷酸苏氨酸的磷酸酶。卤酸脱卤酶结构域的羧基末端含有酪氨酸磷酸酶，氨基末端的一半进行苏氨酸磷酸酶。突变的苏氨酸磷酸酶，但不是酪氨酸磷酸酶，废除EYA 4的能力，以提高先天性免疫反应，表明EYA调节先天性免疫反应，通过调节细胞内病原体的信号转导的磷酸化状态。
Innate immunity is stimulated not only by viral or bacterial components, but also by non-microbial danger signals (damage-associated molecular patterns)(1). One of the damage-associated molecular patterns is chromosomal DNA that escapes degradation. In programmed cell death and erythropoiesis, DNA from dead cells or nuclei expelled from erythroblasts is digested by DNase II in the macrophages after they are engulfed. DNase II-/- (also known as Dnase2a(-/-)) mice suffer from severe anaemia or chronic arthritis due to interferon-beta (IFN-beta) and tumour necrosis factor-alpha (TNF-alpha) produced from the macrophages carrying undigested DNA(2,3) in a Toll-like receptor (TLR)-independent mechanism(4). Here we show that Eyes absent 4 (EYA4), originally identified as a co-transcription factor, stimulates the expression of IFN-beta and CXCL10 in response to the undigested DNA of apoptotic cells. EYA4 enhanced the innate immune response against viruses (Newcastle disease virus and vesicular stomatitis virus), and could associate with signalling molecules (IPS-1 (also known as MAVS), STING (TMEM173) and NLRX1). Three groups have previously shown that EYA has phosphatase activity(5-7). We found that mouse EYA family members act as a phosphatase for both phosphotyrosine and phosphothreonine. The haloacid dehalogenase domain at the carboxy terminus contained the tyrosine-phosphatase, and the amino-terminal half carried the threonine-phosphatase. Mutations of the threonine-phosphatase, but not the tyrosine-phosphatase, abolished the ability of EYA4 to enhance the innate immune response, suggesting that EYA regulates the innate immune response by modulating the phosphorylation state of signal transducers for the intracellular pathogens.