Microbial gasdermins: More than a billion years of pyroptotic-like cell death

In the recent past, the concept of immunity has been extended to eukaryotic and prokaryotic microorganisms, like fungi and bacteria. The latest findings have drawn remarkable evolutionary parallels between metazoan and microbial defense-related genes, unveiling a growing number of shared transkingdom components of immune systems. One such component is the gasdermin family of pore-forming proteins - executioners of a highly inflammatory immune cell death program in mammals, termed pyroptosis. Pyroptotic cell death limits the spread of intracellular pathogens by eliminating infected cells and coordinates the broader inflammatory response to infection. The microbial gasdermins have similarly been implicated in defense-related cell death reactions in fungi, bacteria and archaea. Moreover, the discovery of the molecular regulators of gasdermin cytotoxicity in fungi and bacteria, has established additional evolutionary links to mammalian pyroptotic pathways. Here, we focus on the gasdermin proteins in microorganisms and their role in organismal defense and provide perspective on this remarkable case study in comparative immunology.