A fungal prion is a prion that infects fungal hosts. As other prions, fungal prions are naturally occurring proteins that can undergo a structural conversion that becomes self-propagating and infectious, and they represent an epigenetic phenomenon in which information is not encoded in the nuclear DNA, but is structurally encoded within the protein itself. Several prion-forming proteins have been identified in fungi, primarily in the yeast Saccharomyces cerevisiae. Some of these are not associated with any disease state and may possibly have a beneficial role by giving an evolutionary advantage to their host.
Fungal prions provide a model for the understanding of disease-forming mammalian prions.
The HET-s Prion of Podospora anserina
Podospora anserina is a filamentous fungus. Genetically compatible colonies of this fungus can merge and share cellular contents such as nutrients and cytoplasm. A natural system of protective "incompatibility" proteins exists to prevent promiscuous sharing between unrelated colonies. One such protein, called HET-s, adopts a prion-like form in order to function properly. The prion form of HET-s spreads rapidly throughout the cellular network of a colony and can convert the non-prion form of the protein to a prion state after compatible colonies have merged. However, when an incompatible colony tries to merge with a prion-containing colony, the prion causes the "invader" cells to die, ensuring that only related colonies obtain the benefit of sharing resources.
Prions of Yeast
[PSI+] & [URE3]
In 1965, Brian Cox, a geneticist working with the yeast Saccharomyces cerevisiae, described a genetic trait (termed [PSI+]) with an unusual pattern of inheritance. The initial discovery of [PSI+] was made in a strain auxotrophic for adenine due to a nonsense mutation. Despite many years of effort, Cox could not identify a conventional mutation that was responsible for the [PSI+] trait. In 1994, yeast geneticist Reed Wickner correctly hypothesized that [PSI+] as well as another mysterious heritable trait, [URE3], resulted from prion forms of the normal cellular proteins, Sup35p and Ure2p, respectively. The names of yeast prions are frequently placed within brackets to indicate that they are non-mendelian in their passage to progeny cells, much like plasmid and mitochondrial DNA.
Further investigation found that [PSI+] is the result of a self-propagating misfolded form of Sup35p (a 201 amino acid long protein), which is an important factor for translation termination during protein synthesis. In [PSI+] yeast cells the Sup35 protein forms filamentous aggregates known as amyloid. The amyloid conformation is self-propagating and represents the prion state. It is believed that suppression of nonsense mutations in [PSI+] cells is due to a reduced amount of functional Sup35 because much of the protein is in the amyloid state. The Sup35 protein assembles into amyloid via an amino-terminal prion domain. The structure is based on the stacking of the prion domains in an in-register and parallel beta sheet conformation.
When exposed to certain adverse conditions, in some genetic backgrounds [PSI+] cells actually fare better than their prion-free siblings; this finding suggests that the ability to adopt a [PSI+] prion form may result from positive evolutionary selection. It has been speculated that the ability to convert between prion-infected and prion-free forms acts as an evolutionary capacitor to enable yeast to quickly and reversibly adapt in variable environments. Nevertheless, Reed Wickner maintains that URE3 and [PSI+] are diseases, although this claim has been challenged using theoretical population genetic models.
Protein chaperones assist protein folding and stability, and are intimately linked to the inheritance and transmission of [PSI+] and many other yeast prions. Because of the action of chaperones, especially Hsp104, proteins that code for [PSI+] and [URE3] can convert between prion and non-prion forms, resulting in the reversibility of prion formation. For this reason, yeast prions are good models for studying factors like chaperones that affect protein aggregation. Also, the IPOD is the sub-cellular site to which amyloidogenic proteins are sequestered in yeast, and where prions like [PSI+] may undergo maturation. Thus, prions also serve as substrates to understand the intracellular processing of protein aggregates such as amyloid.
Laboratories commonly identify [PSI+] by growth of a strain auxotrophic for adenine on media lacking adenine, similar to that used by Cox et al. These strains cannot synthesize adenine due to a nonsense mutation in one of the enzymes involved in the biosynthetic pathway. When the strain is grown on yeast-extract/dextrose/peptone media (YPD), the blocked pathway results in buildup of a red-colored intermediate compound, which is exported from the cell due to its toxicity. Hence, color is an alternative method of identifying [PSI+] -- [PSI+] strains are white or pinkish in color, and [psi-] strains are red. A third method of identifying [PSI+] is by the presence of Sup35 in the pelleted fraction of cellular lysate.
[PIN+] / [RNQ+]
The term [PIN+] is commonly used to indicate the prion form of Rnq1. For the induction of most variants of the [PSI+] prion, the presence of [PIN+] is required. A non-prion function of Rnq1 has not been definitively characterized. Though reasons for this are poorly understood, it is suggested that [PIN+] aggregates may act as "seeds" for the polymerization of [PSI+] and other prions. Like Sup35 and Ure2, the basis of the [PIN+] prion is an amyloid form of Rnq1. The amyloid is composed of the Rnq1 protein arranged in in-register parallel beta sheets, like the amyloid form of Sup35. Due to similar amyloid structures, the [PIN+] prion may facilitate the formation of [PSI+] through a templating mechanism.
The term [PIN+] is derived from Psi-INducibility, because [PIN+] facilitates the formation of the [PSI+] prion. The more precise name [RNQ+] is now frequently used because other factors or prions can also have a Psi-inducing phenotype. Two modified versions of Sup35 have been created that can induce PSI+ in the absence of [PIN+] when overexpressed. One version was created by digestion of the gene with BalI, which results in a protein consisting of only the M and N portions of Sup35. The other is a fusion of Sup35NM with HPR, a human membrane receptor protein.
List of Characterized Prions
|Protein||Natural Host||Normal Function||Prion State||Prion Phenotype||Year Identified|
|Ure2p||Saccharomyces cerevisiae||Nitrogen catabolite repressor||[URE3]||Growth on poor nitrogen sources||1994|
|Sup35p||Saccharomyces cerevisiae||Translation termination factor||[PSI+]||Increased levels of nonsense suppression||1994|
|HET-S||Podospora anserina||Regulates heterokaryon incompatibility||[Het-s]||Heterokaryon formation between incompatible strains||1997|
|vacuolar protease B||Saccharomyces cerevisiae||death in stationary phase, failure in meiosis||[β]||failure to degrade cellular proteins under N starvation||2003|
|MAP kinases||Podospora anserina||increased pigment, slow growth||[C]||2006|
|Rnq1p||Saccharomyces cerevisiae||Protein template factor||[RNQ+],[PIN+]||Promotes aggregation of other prions||2008|
|Mca1*||Saccharomyces cerevisiae||Putative Yeast Caspase||[MCA+]||Unknown||2008|
|Swi1||Saccharomyces cerevisiae||Chromatin remodeling||[SWI+]||Poor growth on some carbon sources||2008|
|Cyc8||Saccharomyces cerevisiae||Transcriptional repressor||[OCT+]||Transcriptional derepression of multiple genes||2009|
|Mot3||Saccharomyces cerevisiae||Nuclear transcription factor||[MOT3+]||Transcriptional derepression of anaerobic genes||2009|
|Pma1+Std1 ||Saccharomyces cerevisiae||Pma1 = major plasma membrane proton pump, Std1=minor pump||[GAR+]||Resistant to glucose-associated repression||2009|
|Sfp1 ||Saccharomyces cerevisiae||Global transcriptional regulator||[ISP+]||Antisuppressor of certain sup35 mutations||2010|
|Mod5 ||Saccharomyces cerevisiae||[MOD+]||2012|
[*The original paper that proposed Mca1 is a prion was retracted ]
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