Environmental Regulation of Prions in Yeast

The term prion, proteinaceus infectious particle, was first used to describe the causative agent of a group of mammalian neurodegenerative diseases known as transmissible spongiform encephalopathies (TSEs) [1]. The mammalian prion protein (PrP) can exist in either a normal cellular conformation, PrP, or in multiple misfolded pathogenic conformations, collectively called PrP. PrP is considered infectious because it can recruit and convert its normal isomer PrP to its pathogenic conformation. This ‘‘protein-only’’ concept of infectivity has gained general acceptance and has been extended to explain some unusual nonMendelian genetic elements in the budding yeast Saccharomyces cerevisiae. In yeast, these factorsare transmitted from mother to daughter cell as particular self-propagating protein conformations, and are thus referred to as yeast prions [2]. Yeast prions share many features with PrP: both are capable of perpetuating particular conformational changes, forming amyloid fibrils (ordered protein aggregates with cross-b sheet structure and filamentous morphology) under physiological conditions, and both can exist as multiple ‘‘strains’’ or variants. However, a number of fundamental differences between them are worth noting. First, yeast prion proteins and PrP do not share a significant sequence similarity. Almost all yeast prion proteins contain a domain with an unusually high content of glutamine (Q) and asparagine (N) residues (,45%), whereas PrP does not have such a region. The Q/N-rich domains of yeast prion proteins, termed prion forming domains (PrDs), are modular and transferrable and essential for the formation and propagation of their corresponding prions. Second, whereas the normal function of PrP is unclear, yeast prion proteins are involved in a wide range of functions, from transcriptional and translational regulation to nitrogen metabolism. To date, PrP is the only prion protein identified in mammals, whereas at least 8 prions have been identifiedin yeast: [PSI], [URE3], [PIN], [SWI], [OCT], [MOT3], [ISP], and [MOD] [3,4] (capital letters indicate that these genetic elements are dominant, and brackets signify nonMendelian patterns of inheritance). Finally, while PrP is associated with human disease, yeast prions are not associated with disease per se, but manifest as dominant, cytoplasmically inherited phenotypes.