AIM2 forms a complex with pyrin and ZBP1 to drive PANoptosis and host defence

Inflammasomes are important sentinels of innate immune defence, sensing pathogens and inducing cell death in infected cells'. There are several inflammasome sensorsthat each detect and respond to a specific pathogen- or damage-associated molecular pattern (PAMP or DAMP, respectively)(1). During infection, live pathogens can induce the release of multiple PAMPs and DAMPs, which can simultaneously engage multiple inflammasome sensors(2-5). Here we found that AIM2 regulatesthe innate immune sensors pyrin and ZBP1to drive inflammatory signalling and a form of inflammatory cell death known as PANoptosis, and provide host protection during infections with herpes simplex vi rusl and Francisella novicida. We also observed that AIM2, pyrin and ZBP1 were members of a large multi-protein complex along with ASC, caspase-1, caspase-8, RIPK3, RIPK1 and FADD, that drove inflammatory cell death (PANoptosis). Collectively, our findings define a previously unknown regulatory and molecular interaction between AIM2, pyrin and ZBP1that drives assembly of an AIM2-mediated multi-protein complex that we term the AIM2 PANoptosome and comprising multiple inflammasome sensors and cell death regulators. These results advance the understanding ofthe functions ofthese molecules in innate immunity and inflammatory cell death, suggesting newtherapeutic targets for AIM2-, ZBP1- and pyrin-mediated diseases