AIM2 Recognizes Cytosolic Dsdna and Forms a Caspase-1 Activating Inflammasome with ASC

Cytoplasmic DNA is an important trigger for the innate immune system. The downstream signalling pathways involved in this process have been extensively characterized, but much less is known about the initial step, the recognition of the DNA. Two groups reporting in this issue of Nature have now identified AIM2 (absent in melanoma 2), a member of the interferon-inducible HIN-200 family, as a cytoplasmic DNA sensor. In the presence of DNA, AIM2 oligermerizes and associates with the adapter molecule ASC to activate NF-κB and caspase-1, key components of the inflammasome complex. This highlights the AIM2 inflammasome as a possible target for the treatment of both infections and autoimmune diseases. This paper shows that the protein AIM2 (absent in melanoma 2) is a receptor of cytoplasmic DNA and the double-stranded DNA vaccinia virus, and is a component of the inflammasome pathway for caspase-1 activation. 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 responses2,3,4,5,6. 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 genes2,3. 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 IL1β 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-κB 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.