Gasdermin and Gasdermin-Like Pore-Forming Proteins in Invertebrates, Fungi and Bacteria.

The gasdermin family of pore-forming proteins (PFPs) has recently emerged as key molecular players controlling immune-related cell death in mammals. Characterized mammalian gasdermins are activated through proteolytic cleavage by caspases or serine proteases, which remove an inhibitory carboxy-terminal domain, allowing the pore-formation process. Processed gasdermins form transmembrane pores permeabilizing the plasma membrane, which often results in lytic and inflammatory cell death. While the gasdermin-dependent cell death (pyroptosis) has been predominantly characterized in mammals, it now has become clear that gasdermins also control cell death in early vertebrates (teleost fish) and invertebrate animals such as corals (Cnidaria). Moreover, gasdermins and gasdermin-like proteins have been identified and characterized in taxa outside of animals, notably Fungi and Bacteria. Fungal and bacterial gasdermins share many features with mammalian gasdermins including their mode of activation through proteolysis. It has been shown that in some cases the proteolytic activation is executed by evolutionarily related proteases acting downstream of proteins resembling immune receptors controlling pyroptosis in mammals. Overall, these findings establish gasdermins and gasdermin-regulated cell death as an extremely ancient mechanism of cellular suicide and build towards an understanding of the evolution of regulated cell death in the context of immunology. Here, we review the broader gasdermin family, focusing on recent discoveries in invertebrates, fungi and bacteria.