Assembly-driven activation of the AIM2 foreign-dsDNA sensor provides a polymerization template for downstream ASC

AIM2 recognizes foreign dsDNA and assembles into the inflammasome, a filamentous supramolecular signalling platform required to launch innate immune responses. We show here that the pyrin domain of AIM2 (AIM2 PYD ) drives both filament formation and dsDNA binding. In addition, the dsDNA-binding domain of AIM2 also oligomerizes and assists in filament formation. The ability to oligomerize is critical for binding dsDNA, and in turn permits the size of dsDNA to regulate the assembly of the AIM2 polymers. The AIM2 PYD oligomers define the filamentous structure, and the helical symmetry of the AIM2 PYD filament is consistent with the filament assembled by the PYD of the downstream adaptor ASC. Our results suggest that the role of AIM2 PYD is not autoinhibitory, but generating a structural template by coupling ligand binding and oligomerization is a key signal transduction mechanism in the AIM2 inflammasome. The AIM2 inflammasome complex is essential for defence against a number of human pathogens but how it assembles upon recognition of foreign DNA remains incompletely understood. Here Morrone et al. suggest the AIM2 pyrin domain acts in both DNA binding and filament assembly to generate a structural template for complex assembly.