Immunology: Caspase target drives pyroptosis.

Abstract

Inflammatory caspase proteins help to control pathogen replication by triggering pyroptotic cell death. It now emerges that cleavage of the caspase substrate gasdermin D is sufficient to induce pyroptosis. See Articles p.660 & p.666 Two groups reporting in this issue of Nature identify gasdermin D, the product of the Gsdmd gene conserved in human and mouse but of unknown function, as a substrate for inflammatory caspases. Feng Shao and co-workers use genome-wide CRISPR–Cas9 screens to identify gasdermin D as a substrate for inflammatory caspases. Caspase-1 and caspase-4/5/11 specifically cleaved the linker between the amino-terminal gasdermin-N and carboxy-terminal gasdermin-C domains. Vishva Dixit and co-workers use an ENU mutagenesis screen to identify gasdermin D as the required substrate for pyroptosis-mediating caspase-11 in the non-canonical inflammasome pathway. Mice lacking gasdermin D are protected from a lethal dose of lipopolysaccharide. Both groups show that the cleaved N-terminal domain is sufficient to trigger pyroptosis, a form of programmed necrotic cell death.