Caspase-mediated LPS sensing and pyroptosis signaling in Hydra

Inflammatory caspases sensing lipopolysaccharide (LPS) to drive gasdermin (GSDM)-mediated Pyroptosis is an important immune response mechanism for Anti-infection defense in mammals. In this work, we resolved an LPS-induced and GSDM-gated Pyroptosis signaling cascade in Cnidarians. Initially, we identified a functional GSDM protein, HyGSDME, in Hydra, executing cytosolic LPS-induced Pyroptosis in a caspase-dependent manner. Further, we identified a proinflammatory Caspase, HyCaspA, capable of sensing cytosolic LPS by an uncharacterized N-terminal domain relying on its unique hydrophobic property, thereby triggering its oligomerization and self-activation. Subsequently, the LPS-activated HyCaspA cleaved an apoptotic Caspase, HyCARD2, to trigger HyGSDME-gated Pyroptosis. Last, HyGSDME exhibited an enriched distribution on the ectodermal layer of Hydra polyps, exerting a canonical immune defense function against surface-invading bacteria. Collectively, our work resolved an ancient Pyroptosis signaling cascade in Hydra, suggesting that inflammatory caspases sensing cytosolic LPS to initiate GSDM-gated Pyroptosis are a conserved immune defense mechanism from Cnidarians to mammals.