Yeast PrionEdit
Yeast prions are heritable, protein-based elements that can alter the phenotype of Saccharomyces cerevisiae without changing the underlying DNA sequence. In yeast, a small group of prion-forming proteins can adopt an alternative, self-templating conformation that self-propagates through cell divisions. The best-characterized examples are the prions generated by Sup35, Ure2, and RNQ1, which correspond to the PSI+, URE3, and PIN+ phenotypes, respectively. These states are underpinned by amyloid-like aggregates that can template the conversion of normal, soluble protein into the prion form, thereby creating a heritable, non-genetic source of variation. The discovery of yeast prions established a tractable model for studying epigenetic inheritance driven by protein conformation, and it connected protein folding, cellular stress responses, and heredity in new ways. Prion Epigenetics Protein folding Amyloid Saccharomyces cerevisiae
Mechanisms and biology
Protein conformational templating: In the prion state, a fraction of the native protein adopts an aggregated, beta-rich conformation that can recruit additional soluble copies to convert them, propagating the state across generations. This templating mechanism is a hallmark of prions and is central to how the phenotype is inherited independently of the genome. The concept is studied in the context of Sup35 for the PSI+ state, Ure2 for the URE3 state, and RNQ1 for the PIN+ state. Sup35 Ure2 RNQ1
Chaperone machinery and propagation: Propagation of yeast prions depends on cellular chaperone networks. In particular, the ATPase Hsp104 fragments prion fibers into propagons, which are then inherited by daughter cells. Other chaperones, like Hsp70 (the Ssa family) and Hsp40 family members (such as Ydj1 and Sis1), assist in remodeling prion aggregates and maintaining the prion state. Disruption of this network can cure cells of prions, providing a useful experimental handle on the biology of these elements. Hsp104 Hsp70 Hsp40 Ydj1 Sis1
Canonical prions in yeast:
- PSI+ alters translation termination by enabling read-through of stop codons, which can reveal phenotypic variation that is normally suppressed. This effect is linked to the sequestration of Sup35, a translation termination factor. PSI+ Sup35
- URE3 changes nitrogen metabolism regulation by sequestering Ure2, altering metabolic gene expression and growth under different nitrogen sources. URE3 Ure2
- PIN+ (often associated with RNQ1) modulates prion formation and can influence the appearance of PSI+ through cross-seeding mechanisms. PIN+ RNQ1
Epigenetic inheritance and reversibility: Prion states are inherited through cytoplasm during cell division, but they can be reversed or cured by changing growth conditions or chemical treatments (for example, guanidine hydrochloride can disrupt the chaperone machinery necessary for prion maintenance). This demonstrates a non-DNA-based, yet heritable form of information that sits alongside genetic inheritance. Epigenetics Guanidine hydrochloride
Evolutionary and biological significance
Phenotypic diversity without genotype change: Yeast prions generate heritable phenotypic variation in populations facing changing environments. This can act as a bet-hedging strategy, allowing a subset of cells to explore alternative expression states that might be advantageous under stress. Researchers study how such variation interacts with natural selection and genetic diversity in yeast populations. Non-Mendelian inheritance Evolution Saccharomyces cerevisiae
Adaptive potential versus burden: Some prion states may confer advantages in particular ecological contexts (for example, faster adaptation to fluctuating nutrient conditions), while others impose metabolic costs or reduce fitness in stable environments. This balance is a topic of ongoing investigation among scientists studying yeast genetics and protein homeostasis in cells. PSI+ URE3 PIN+
Controversies and debates
Definitions and scope: A longstanding discussion centers on what counts as a prion in yeast and how broadly the term should be applied beyond classic cases like PSI+ and URE3. Some researchers emphasize strict requirements for infectious prion spread and stable propagation, while others advocate for a broader view that includes prion-like amyloids and protein-based inheritance that may not always meet all canonical criteria. Prion Amyloid
Reproducibility and interpretation: As with any unusual mode of inheritance, there have been debates about experimental artifacts, the role of overexpression, and how often natural isolates harbor functional prions versus laboratory-induced states. Careful curing experiments, cross-breeding analyses, and multiple independent demonstrations are used to validate prion phenomena. Non-Mendelian inheritance Saccharomyces cerevisiae
Relevance to higher organisms: Yeast prions have provided models to study prion biology, protein misfolding, and cellular stress responses. However, translating these findings to higher eukaryotes—where prion-like mechanisms and prion diseases exist—remains a subject of interpretation and caution. The extent to which yeast prion biology informs mammalian systems is an active area of inquiry, with ongoing work to distinguish conserved principles from organism-specific details. Prion Amyloid Epigenetics
Practical and research implications
Model systems for heredity and protein folding: Yeast prions are valuable experimentally because they can be studied in well-controlled genetic backgrounds, with rapid generation times and robust genetic tools. They provide a clear link between protein conformation and heritable phenotype, helping researchers dissect the interplay of protein folding, chaperones, and cellular physiology. Saccharomyces cerevisiae Hsp104 Chaperones
Biotechnology and systems biology: Understanding how prions propagate and influence cell physiology informs broader work on protein quality control, stress responses, and cellular adaptation. These insights have relevance for fields ranging from industrial fermentation to synthetic biology, where controlling phenotypic variability can be advantageous. Protein folding Epigenetics Non-Mendelian inheritance