AIM2 recognizes cytosolic dsDNA and forms a caspase-1 activating inflammasome with ASC. The study identifies AIM2, a member of the PYHIN family, as a receptor for cytosolic DNA that regulates caspase-1 activation. The HIN200 domain of AIM2 binds to DNA, while the PYD domain interacts with the adapter molecule ASC to activate both NF-κB and caspase-1. Knockdown of AIM2 abrogates caspase-1 activation in response to cytoplasmic dsDNA and the dsDNA virus, vaccinia. These findings demonstrate that AIM2 forms an inflammasome with ASC to activate caspase-1, leading to the processing of pro-IL-1β. The study also shows that AIM2 is required for the innate immune response to vaccinia virus. AIM2 directly binds to dsDNA, and its interaction with ASC is essential for inflammasome activation. The study further reveals that AIM2 is involved in the recognition of dsDNA and that its absence leads to increased type I IFN induction and resistance to poly(dA-dT)-induced cell death. The results highlight the role of AIM2 in sensing cytosolic DNA and activating the inflammasome, which is crucial for innate immunity to viral infections. The study also suggests that AIM2 may play a role in autoimmune diseases due to its involvement in the IL-1β pathway. Overall, the study identifies AIM2 as a novel receptor for cytosolic DNA that forms an inflammasome with ASC to activate caspase-1 and regulate inflammatory responses.AIM2 recognizes cytosolic dsDNA and forms a caspase-1 activating inflammasome with ASC. The study identifies AIM2, a member of the PYHIN family, as a receptor for cytosolic DNA that regulates caspase-1 activation. The HIN200 domain of AIM2 binds to DNA, while the PYD domain interacts with the adapter molecule ASC to activate both NF-κB and caspase-1. Knockdown of AIM2 abrogates caspase-1 activation in response to cytoplasmic dsDNA and the dsDNA virus, vaccinia. These findings demonstrate that AIM2 forms an inflammasome with ASC to activate caspase-1, leading to the processing of pro-IL-1β. The study also shows that AIM2 is required for the innate immune response to vaccinia virus. AIM2 directly binds to dsDNA, and its interaction with ASC is essential for inflammasome activation. The study further reveals that AIM2 is involved in the recognition of dsDNA and that its absence leads to increased type I IFN induction and resistance to poly(dA-dT)-induced cell death. The results highlight the role of AIM2 in sensing cytosolic DNA and activating the inflammasome, which is crucial for innate immunity to viral infections. The study also suggests that AIM2 may play a role in autoimmune diseases due to its involvement in the IL-1β pathway. Overall, the study identifies AIM2 as a novel receptor for cytosolic DNA that forms an inflammasome with ASC to activate caspase-1 and regulate inflammatory responses.