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-β, 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 1β 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 1β showed that AIM2 was sufficient for inflammasome activation. Our data suggest that AIM2 is a cytoplasmic DNA sensor for the inflammasome.
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We acknowledge O. Hantschel and A. Pichlmair for critical reading of the manuscript, and M. Brehme for help with illustrations. Supported by the Austrian Academy of Sciences (for the Research Center for Molecular Medicine), the GenAU Program of the Austrian Federal Ministry of Science and Research (Austrian Proteomics Platform II (GZ200.145/I-VI/I/2006) and DRAGON (GZ200.142/I-VI/I/2006)), the European Commission (PIEF-GA-2008-220596 to C.B.) and the Austrian Science Fund (FWF W1205 to E.D.).
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