Nature. 2009 Mar 26;458(7237):514-8. Epub 2009 Jan 21.

AIM2 recognizes cytosolic dsDNA and forms a caspase-1-activating inflammasome with ASC.External

Hornung, V., Ablasser, A., Charrel-Dennis, M., Bauernfeind, F., Horvath, G., Caffrey, D. R., Latz, E., Fitzgerald, K. A.,
--- - Division of Infectious Diseases and Immunology, Department of Medicine, University of Massachusetts Medical School, Worcester, Massachusetts 01605, USA. veit.hornung@uni-bonn.de
The innate immune system senses nucleic acids by germline-encoded pattern recognition receptors. RNA is sensed by Toll-like receptor members TLR3, TLR7 and TLR8, or by the RNA helicases RIG-I (also known as DDX58) and MDA-5 (IFIH1). Little is known about sensors for cytoplasmic DNA that trigger antiviral and/or inflammatory responses. The best characterized of these responses involves activation of the TANK-binding kinase (TBK1)-interferon regulatory factor 3 (IRF3) signalling axis to trigger transcriptional induction of type I interferon genes. A second, less well-defined pathway leads to the activation of an 'inflammasome' that, via caspase-1, controls the catalytic cleavage of the pro-forms of the cytokines IL1beta and IL18 (refs 6, 7). Using mouse and human cells, here we identify the PYHIN (pyrin and HIN domain-containing protein) family member absent in melanoma 2 (AIM2) as a receptor for cytosolic DNA, which regulates caspase-1. The HIN200 domain of AIM2 binds to DNA, whereas the pyrin domain (but not that of the other PYHIN family members) associates with the adaptor molecule ASC (apoptosis-associated speck-like protein containing a caspase activation and recruitment domain) to activate both NF-kappaB and caspase-1. Knockdown of Aim2 abrogates caspase-1 activation in response to cytoplasmic double-stranded DNA and the double-stranded DNA vaccinia virus. Collectively, these observations identify AIM2 as a new receptor for cytoplasmic DNA, which forms an inflammasome with the ligand and ASC to activate caspase-1.
PMID: 19158675External
Arrow2 In vitro interaction Arrow2 In vivo interaction Arrow2 Characterization Arrow2 Functional role Arrow2 top
In vivo interaction
  Endogenous
expression
Overexpression DD1 DD2 Reference
Family DD1 DD2 Method Species Region Species Region
PYD AIM2 Link ASC Co-immunoprecipitation HEK293 Human 1-83 Human Not specified 19158675
PYD AIM2 Link ASC Fluorescence resonance energy transfer HEK293 Human Full length Human Not specified 19158675
PYD AIM2 Link ASC Fluorescence resonance energy transfer HEK293 Human 1-83 Human Not specified 19158675
PYD ASC Link NLRP3 Co-immunoprecipitation HEK293 Human Not specified Not specified 1-87 19158675
PYD ASC Link NLRP3 Fluorescence resonance energy transfer HEK293 Human Not specified Not specified 1-87 19158675
(Link: click this icon to show interactions only between the two corresponding DDs)
Arrow2 In vitro interaction Arrow2 In vivo interaction Arrow2 Characterization Arrow2 Functional role Arrow2 top
Functional Role
Family DD1 DD2 Method Death-related Death-unrelated Reference
PYD AIM2 Link ASC Luciferase assay NF-kB activation (Inflammasome) 19158675
(Link: click this icon to show interactions only between the two corresponding DDs)