Fungal gasdermin-like proteins are controlled by proteolytic cleavage

Significance The recent discovery of gasdermin-like proteins in fungi have brought to light that this family of pore-forming proteins controls cell death in two of the major eukaryotic kingdoms, fungi and mammals. Yet the regulation of cytotoxicity of the fungal gasdermins and their molecular pathways remain uncharacterized. Here, we describe the regulation through proteolytic cleavage of the fungal gasdermin HET-Q1 and uncover that a majority of fungal gasdermins are genomically clustered with protease-encoding genes. Some of these genes encode proteins with caspase-related domains and/or are members of a family of immune receptors in mammals and plants. Overall, this work contributes toward our understanding of the evolution of gasdermin-dependent cell death, enlightening multiple evolutionary parallels between signaling pathways in mammals and fungi.