Cell death pathway leading to vacuole permeabilization

PROJECT SUMMARY Programmed cell death (self-induced) is intrinsic to cellular life, including unicellular species. However, cell death research has focused primarily on animal models to understand cancer, degenerative disorders, and developmental processes. In contrast, there is comparably little knowledge of how prokaryotic and eukaryotic microbes die, and cell death mechanisms in human fungal pathogens (multi- or unicellular) are nearly unstudied. Over a million fungal infections are diagnosed annually, many causing significant mortality, and resistance to conventional therapies continues to increase. Building on the principles of cell death discovered in the metazoan cell death field, we propose to characterize novel cell death pathways in unicellular fungal species using the tractable Saccharomyces cerevisiae model system. Targeted genetic approaches, cell biological and biochemical approaches will be used to dissect a vesicle trafficking cell death pathway in yeast that results in lysosome/vacuole membrane permeabilization and cell death, with implications for the human pathogen Cryptococcus neoformans. This new mechanistic understanding is intended to provide fundamental knowledge needed for the future development of new therapeutic strategies analogous to successes in targeted cancer therapy by inducing intrinsic cell death mechanisms.