Bürckstümmer Tilmann, Baumann Christoph, Blüml Stephan, Dixit Evelyn, Dürnberger Gerhard, Jahn Hannah, Planyavsky Melanie, Bilban Martin, Colinge Jacques, Bennett Keiryn L, Superti-Furga Giulio
Research Center for Molecular Medicine of the Austrian Academy of Sciences, 1090 Vienna, Austria.
Nat Immunol. 2009 Mar;10(3):266-72. doi: 10.1038/ni.1702. Epub 2009 Jan 21.
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 1beta 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 1beta showed that AIM2 was sufficient for inflammasome activation. Our data suggest that AIM2 is a cytoplasmic DNA sensor for the inflammasome.
细胞质DNA可触发先天免疫系统的激活。尽管“下游”信号传导成分已得到鉴定，但DNA传感成分仍不清楚。在此，我们对与DNA结合的蛋白质进行了系统的蛋白质组学筛选，并与干扰素-β诱导的转录本筛选“交叉”，从而确定AIM2为候选细胞质DNA传感器。AIM2对双链DNA具有特异性。它还招募炎性小体接头蛋白ASC，并定位于ASC“斑点”。RNA介导的干扰导致AIM2表达下降，损害了THP-1人单核细胞中DNA诱导的白细胞介素1β成熟，这表明内源性AIM2是DNA识别所必需的。用AIM2、ASC、半胱天冬酶-1和白细胞介素1β对无反应的HEK293细胞进行重建，表明AIM2足以激活炎性小体。我们的数据表明，AIM2是炎性小体的细胞质DNA传感器。
