1. Division of Infectious Diseases and Immunology, Department of Medicine, University of Massachusetts Medical School, Worcester, Massachusetts 01605, USA
2. Institute of Clinical Chemistry and Pharmacology, Universitätsklinikum Bonn 53127, Germany
3. Pfizer, 620 Memorial Drive, Cambridge, Massachusetts 02139, USA
4. These authors contributed equally to this work.

Correspondence to: Veit Hornung^1,2Katherine A. Fitzgerald^1,4 Correspondence and requests for materials should be addressed to K.A.F. (Email: kate.fitzgerald@umassmed.edu) or V.H. (Email: veit.hornung@uni-bonn.de).

Abstract

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)¹. Little is known about sensors for cytoplasmic DNA that trigger antiviral and/or inflammatory responses^{2, 3, 4, 5, 6}. 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^{2, 3}. 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 IL1 and IL18 (refs 6, 7). Using mouse and human cells, here we identify the PYHIN (pyrin and HIN domain-containing protein)⁸ 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-B 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.

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