Ancient origins of inflammatory cell death in bacterial immune systems

Gasdermins are important components of the human innate immune response to pathogens. Following pathogen infection, gasdermin proteins are activated by caspases which cleave an inhibitory C-terminal domain. Activated gasdemins form large membrane pores in human cells, which release immune cytokines and induce lytic cell death. While gasdermin proteins were discovered in animals and other eukaryotes, their evolutionary origin remains elusive. Here we discover diverse gasdermin homologs encoded in bacteria and archaea that execute prokaryotic cell death and defend against phage infection. We demonstrate that bacterial gasdermins are activated by dedicated caspase-like proteases that catalyze site-specific cleavage and removal of an inhibitory C-terminal peptide. Release of autoinhibition induces the assembly of membrane pores that disrupt membrane integrity leading to cell death in bacteria. These results demonstrate that the protease-mediated activation of gasdermins is an ancient immune mechanisms of regulated cell death that is conserved across the tree of life.