AIM2 forms a complex with Pyrin and ZBP1 to drive PANoptosis and host defense

Inflammasomes are important sentinels of innate immune defense, sensing pathogens and inducing cell death in infected cells(1). There are several inflammasome sensors that each detect and respond to specific pathogen- and damage-associated molecular patterns (PAMPs and DAMPs)(1). In contrast to this one PAMP/DAMP to one sensor specificity, during infection, live pathogens can induce the release of multiple PAMPs and DAMPs, which could contemporaneously engage multiple inflammasome sensors(2–5). Here we discovered that AIM2 regulated the innate immune sensors Pyrin and ZBP1 to drive inflammatory signaling and inflammatory cell death, PANoptosis, and provide host protection during infections with herpes simplex virus 1 (HSV1) 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. Collectively, our findings define a previously unknown regulatory connection and molecular interaction among AIM2, Pyrin and ZBP1 that drives assembly of an AIM2-mediated multi-protein complex that involves multiple inflammasome sensors and cell death regulators. These results represent a new paradigm in understanding the functions of these molecules in innate immunity and inflammatory cell death, suggesting new therapeutic targets for AIM2-, ZBP1- and Pyrin-mediated diseases.