The study identifies AIM2 (absent in melanoma 2) as a receptor for cytosolic double-stranded DNA (dsDNA) that forms an inflammasome with the adapter molecule ASC to activate caspase-1. AIM2's HIN200 domain binds to DNA, while its PYD domain associates with ASC to form a complex that activates both NF-κB and caspase-1. Knockdown of AIM2 abrogates caspase-1 activation in response to cytoplasmic dsDNA and the dsDNA virus, vaccinia. The findings suggest that AIM2 plays a crucial role in innate immunity to dsDNA and the dsDNA virus vaccinia.The study identifies AIM2 (absent in melanoma 2) as a receptor for cytosolic double-stranded DNA (dsDNA) that forms an inflammasome with the adapter molecule ASC to activate caspase-1. AIM2's HIN200 domain binds to DNA, while its PYD domain associates with ASC to form a complex that activates both NF-κB and caspase-1. Knockdown of AIM2 abrogates caspase-1 activation in response to cytoplasmic dsDNA and the dsDNA virus, vaccinia. The findings suggest that AIM2 plays a crucial role in innate immunity to dsDNA and the dsDNA virus vaccinia.