An orthogonal proteomic-genomic screen identifies AIM2 as a cytoplasmic DNA sensor for the inflammasome.
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.
Bürckstümmer
Tilmann
T
Research Center for Molecular Medicine of the Austrian Academy of Sciences, 1090 Vienna, Austria.
Baumann
Christoph
C
Blüml
Stephan
S
Dixit
Evelyn
E
Dürnberger
Gerhard
G
Jahn
Hannah
H
Planyavsky
Melanie
M
Bilban
Martin
M
Colinge
Jacques
J
Bennett
Keiryn L
KL
Superti-Furga
Giulio
G
D048868:Adaptor Proteins, Signal Transducing / Q000276:immunology / Q000378:metabolism; D000818:Animals; D020170:Caspase 1 / Q000276:immunology / Q000378:metabolism; D003600:Cytosol / Q000378:metabolism; D004247:DNA / Q000276:immunology / Q000378:metabolism*; D004268:DNA-Binding Proteins; D020869:Gene Expression Profiling; D023281:Genomics / Q000379:methods; D006801:Humans; D007113:Immunity, Innate; D016899:Interferon-beta / Q000276:immunology / Q000378:metabolism; D053583:Interleukin-1beta / Q000276:immunology / Q000378:metabolism; D051379:Mice; D041681:NIH 3T3 Cells; D009687:Nuclear Proteins / Q000276:immunology / Q000378:metabolism*; D040901:Proteomics / Q000379:methods
C410167:AIM2 protein, human; D048868:Adaptor Proteins, Signal Transducing; D004268:DNA-Binding Proteins; D053583:Interleukin-1beta; D009687:Nuclear Proteins; D016899:Interferon-beta; D004247:DNA; D020170:Caspase 1