Although prions are infectious agents with a bad reputation, research suggests that prions also play a role in epigenetic regulation. Recently, a Nature Cell Biology study conducted by molecular biologists at the University of Illinois at Chicago, discovered a new prion in yeast that raises further questions about the biological role of prions in gene regulation.
Prions are most simply defined as misfolded infectious proteins. Prion diseases or, “Transmissible Spongiform Encephalopathies” (TSEs) are a group of neurodegenerative disorders that occur in humans and other mammals. The host prion protein (PrP) is the native precursor to the harmful prion conformation. During prion pathogenesis, the initial native soluble form of the protein is converted to the insoluble amyloid conformation. These amyloids form aggregates of fibrous proteins which eventually lead to amyloidosis—the cause of ataxic neurodegenerative symptoms.
As with viral and bacterial pathogens, prions are capable of replication. However, they do so with no involvement of nucleic acids. Prions instead, convert native forms of their corresponding protein into more prions. Furthermore, prions come in different strains and even exhibit differential specie host preferences.
Prions are classifiable as epigenetic regulators because they are able to modify gene expression through protein interactions, as opposed to first receiving “instructions” provided by nucleic acids.
When a host prion gene is over-expressed, spontaneous formation of prions can occur and this is observed in both yeast and mammals. A previous study by Susan Liebman, distinguished university professor of biological science, exploited this known prion feature in order to discover new yeast prions. While in the process of discovering the [SWI+] prion, her lab also found other potential prion forming candidates. In this present study, Liebman’s team tested these candidates and one of them when over-expressed, gene Cyc8, produces the prion “[OCT+]."
In prior research, a yeast prion that was linked to the chromatin remodeling complex (SWI-SNF) suggested that prions could regulate gene transcription on a massive scale. Chromatin is the condensed portion of a chromosome and its formation involves coordination of highly complex protein interactions. Prions would be advantageous for such a task considering structural changes dictated by prions are temporary, reversible and can be completed very quickly (since transcription of genes is not a necessary first step).
The Cyc8 gene (along with Tup1) forms a transcriptional repressor complex responsible for the regulation of over 7% of yeast genes. This protein complex shuts down the expression of numerous genes including some genes that are involved in stress tolerance. As expected, the prion form of the Cyc8 protein causes profound phenotypic effects.
“Once Cyc8 is converted to a prion, it loses that function. This might provide some advantage under stressful conditions. Since the protein represses more than 300 genes, it’s possible the prion form can activate the genes on a mass level and converting the protein into a prion would be an easy way to do it,” explains postdoctoral research associate Basant Patel.
Although [OCT+] can be propagated in a laboratory, the question remains as to if [OCT+] formation can form in yeast naturally.
“We know this prion turns on the expression of genes but we don’t know if the prion forms naturally,” said Liebman. “If it were to form, it would have this effect. But whether it happens out in the wild all the time, we don’t know.”
Presently, Patel and others in Liebman’s lab are conducting tests in order to determine if this molecular mechanism does take place naturally.
To date, scientists have discovered only seven prions, six of which are only found in fungi, including yeast. The discovery of prions acting as epigenetic regulators in yeast begs the question; do humans also have similar prion mechanisms as well? If so, perhaps these hypothetical human prions are related to the prions we find in yeast. This possibility is certainly on the mind of Liebman and her associates.
“There could be prions in humans that are not causing disease but have important effects on the cell or organism,” said Liebman. “They may even be related to the ones we find in yeast. The more we learn about and study, the more information we learn from then; how they arrive, what proteins are needed to maintain them. As we study other models, we have a better idea.”
Cox, B.S. and Tuite, M. F. 2009. Prions remodel gene expression in yeast. Nature Cell Biology 11(3):241-243.
Patel, B. K., Gavin-Smyth, J., Liebman, S. W. 2009. The yeast global transcriptional co-repressor protein Cyc8 can propagate as a prion. Nature Cell Biology 11(3): 344-352.
Prusiner, S. B. 1998. Prions. Proc. Natl. Acad. Sci. USA 95: 13363-13383.