Modeling Necroptotic and Pyroptotic Signaling in Saccharomyces cerevisiae

The yeast Saccharomyces cerevisiae is the paradigm of a eukaryotic model organism. In virtue of a substantial degree of functional conservation, it has been extensively exploited to understand multiple aspects of the genetic, molecular, and cellular biology of human disease. Many aspects of cell signaling in cancer, aging, or metabolic diseases have been tackled in yeast. Here, we review the strategies undertaken throughout the years for the development of humanized yeast models to study regulated cell death (RCD) pathways in general, and specifically, those related to innate immunity and inflammation, with an emphasis on pyroptosis and necroptosis. Such pathways involve the assembly of distinct modular signaling complexes such as the inflammasome and the necrosome. Like other supramolecular organizing centers (SMOCs), such intricate molecular arrangements trigger the activity of enzymes, like caspases or protein kinases, culminating in the activation of lytic pore-forming final effectors, respectively, Gasdermin D (GSDMD) in pyroptosis and MLKL in necroptosis. Even though pathways related to those governing innate immunity and inflammation in mammals are missing in fungi, the heterologous expression of their components in the S. cerevisiae model provides a “cellular test tube” to readily study their properties and interactions, thus constituting a valuable tool for finding novel therapies.