An orthogonal proteomic-genomic screen identifies AIM2 as a cytoplasmic DNA sensor for the inflammasome
An orthogonal proteomic-genomic screen identifies AIM2 as a cytoplasmic DNA sensor for the inflammasome
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DOI：
10.1038/ni.1702
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发表时间：
2009-03-01
影响因子：
30.5
通讯作者：
Superti-Furga, Giulio
中科院分区：
文献类型：
--
作者：
Buerckstuemmer, Tilmann;Baumann, Christoph;Superti-Furga, Giulio
细胞质DNA触发先天免疫系统的激活。尽管已经表征了“下游”信号传导组件，但DNA感应组件仍然难以捉摸。在这里，我们提出了与DNA相关的蛋白质的系统蛋白质组学筛选，“交叉”到Interferon-beta引起的转录本的屏幕上，该蛋白质将AIM2识别为候选细胞质DNA传感器。 AIM2显示出双链DNA的特异性。它还招募了炎症适配器ASC，并将其本地化为ASC“ Speckles”。 RNA介导的干扰产生的AIM2表达降低了DNA诱导的白介素1β在THP-1人单核细胞中的成熟，这表明内源性AIM2是DNA识别所必需的。用AIM2，ASC，caspase-1和白介素1β对无反应性HEK293细胞重新建立，表明AIM2足以进行炎性体激活。我们的数据表明，AIM2是炎性体的细胞质DNA传感器。
Cytoplasmic DNA triggers activation of the innate immune system. Although 'downstream' signaling components have been characterized, the DNA-sensing components remain elusive. Here we present a systematic proteomics screen for proteins that associate with DNA, 'crossed' to a screen for transcripts induced by interferon-beta, which identified AIM2 as a candidate cytoplasmic DNA sensor. AIM2 showed specificity for double-stranded DNA. It also recruited the inflammasome adaptor ASC and localized to ASC 'speckles'. A decrease in AIM2 expression produced by RNA-mediated interference impaired DNA-induced maturation of interleukin 1 beta in THP-1 human monocytic cells, which indicated that endogenous AIM2 is required for DNA recognition. Reconstitution of unresponsive HEK293 cells with AIM2, ASC, caspase-1 and interleukin 1 beta showed that AIM2 was sufficient for inflammasome activation. Our data suggest that AIM2 is a cytoplasmic DNA sensor for the inflammasome.