Fungal prion
Fungal prions provide an excellent model for the understanding of disease-forming mammalian prions. Fungal prions are naturally occurring proteins that can undergo a structural conversion that becomes self-propagating and infectious. They represent an epigenetic phenomenon in which information is not encoded in the nuclear DNA, but is structurally encoded within the protein. 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.[1]
The HET-s Prion of Podospora anserina
Podospora anserina is a filamentous fungus. Genetically compatible colonies of this fungus can merge together 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.[2] 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.[3] 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.[4] 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 certain normal cellular proteins.[5] 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.
It was soon noticed that heat shock proteins (which help other proteins fold properly) such as Hsp104 were intimately tied to the inheritance and transmission of [PSI+] and many other yeast prions. Since then, researchers have unravelled how the proteins that code for [PSI+] and [URE3] can convert between prion and non-prion forms, as well as the consequences of having intracellular prions.
When exposed to certain adverse conditions, in some genetic backgrounds [PSI+] cells actually fare better than their prion-free siblings;[6] this finding suggests that the ability to adopt a [PSI+] prion form may result from positive evolutionary selection.[7] 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, Wickner maintains that URE3 and [PSI+] are diseases,[8] although this claim has been challenged using theoretical population genetic models.[9]
Further investigation found that [PSI+] is the result of a self-propagating misfolded form of Sup35p, which is an important factor for translation termination during protein synthesis.[10] 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 confirmation.[11]
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 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+]
[PIN+], in turn, is the misfolded form of the protein Rnq1. However, the normal function of this protein is unknown to date. It is of note that for the induction of most variants of [PSI+], the presence of [PIN+] is required. Though reasons for this are poorly understood, it is suggested that [PIN+] aggregates may act as "seeds" for the polymerization of [PSI+].[12] 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.[13] Due to similar amyloid structures, the [PIN+] prion may facilitate the formation of [PSI+] through a templating mechanism.
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.[14] The other is a fusion of Sup35NM with HPR, a human membrane receptor protein.
List of Characterized Fungal Prions
| Fungal 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 | ||
| Rnq1p | Saccharomyces cerevisiae | Protein template factor | [RNQ+],[PIN+] | Promotes aggregation of other prions | ||
| 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 [15] the major plasma membrane proton pump Std1 |
Saccharomyces cerevisiae | [GAR+] | resistant to glucose-associated repression | 2009 | ||
| Sfp1 [16] | Saccharomyces cerevisiae | global transcriptional regulator | [ISP+] | antisuppressor of certain sup35 mutations | 2010 | |
- The original paper that proposed Mca1 is a prion was retracted [17]
References
- ^ Michelitsch MD, Weissman JS. (2000). "A census of glutamine/asparagine-rich regions: implications for their conserved function and the prediction of novel prions". Proc Natl Acad Sci U S A. 97 (22): 11910–5. doi:10.1073/pnas.97.22.11910. PMC 17268. PMID 11050225.
- ^ Coustou V, Deleu C, Saupe S, Begueret J. (1997). "The protein product of the het-s heterokaryon incompatibility gene of the fungus Podospora anserina behaves as a prion analog". Proc Natl Acad Sci U S A. 94 (18): 9773–8. doi:10.1073/pnas.94.18.9773. PMC 23266. PMID 9275200.
{{cite journal}}: CS1 maint: multiple names: authors list (link) - ^ Maddelein ML, Dos Reis S, Duvezin-Caubet S, Coulary-Salin B, Saupe SJ. (2002). "Amyloid aggregates of the HET-s prion protein are infectious". Proc Natl Acad Sci U S A. 99 (11): 7402–7. doi:10.1073/pnas.072199199. PMC 124243. PMID 12032295.
{{cite journal}}: CS1 maint: multiple names: authors list (link) - ^ Cox BS, Tuite MF, McLaughlin CS. (1988). "The psi factor of yeast: a problem in inheritance". Yeast. 4 (3): 159–78. doi:10.1002/yea.320040302. PMID 3059716.
{{cite journal}}: CS1 maint: multiple names: authors list (link) - ^ Wickner RB. (1994). "[URE3] as an altered URE2 protein: evidence for a prion analog in Saccharomyces cerevisiae.". Science. 264 (5158): 566–9. doi:10.1126/science.7909170. PMID 7909170.
- ^ True HL, Lindquist SL. (2000). "A yeast prion provides a mechanism for genetic variation and phenotypic diversity". Nature. 407 (6803): 477–83. doi:10.1038/35035005. PMID 11028992.
- ^ Lancaster AK, Bardill JP, True HL, Masel J (2010). "The Spontaneous Appearance Rate of the Yeast Prion [PSI+] and Its Implications for the Evolution of the Evolvability Properties of the [PSI+] System". Genetics. 184 (2): 393–400. doi:10.1534/genetics.109.110213. PMC 2828720. PMID 19917766.
{{cite journal}}: CS1 maint: multiple names: authors list (link) - ^ Nakayashiki T, Kurtzman CP, Edskes HK, Wickner RB. (2005). "Yeast prions [URE3] and [PSI+] are diseases". Proc Natl Acad Sci U S A. 102 (30): 10575–80. doi:10.1073/pnas.0504882102. PMC 1180808. PMID 16024723.
{{cite journal}}: CS1 maint: multiple names: authors list (link) - ^ Griswold CK, Masel J (2009). "The Strength of Selection Against the Yeast Prion [PSI+]". Genetics. 181 (3): 1057–1063. doi:10.1534/genetics.108.100297. PMC 2651042. PMID 19153253.
- ^ Paushkin, S. V., Kushnirov V. V., Smirnov V. N., Ter-Avanesyan M. D. (1996). "Propagation of the yeast prion-like PSI+ determinant is mediated by oligomerization of the SUP35-encoded polypeptide chain release factor". EMBO Journal. 15 (12): 3127–34. PMC 450255. PMID 8670813.
{{cite journal}}: CS1 maint: multiple names: authors list (link) - ^ Shewmaker F, Wickner RB, Tycko R (2006). "Amyloid of the prion domain of Sup35p has an in-register parallel beta-sheet structure". Proc Natl Acad Sci U S A. 103 (52): 19754–9. doi:10.1073/pnas.0609638103. PMC 1750918. PMID 17170131.
{{cite journal}}: Unknown parameter|month=ignored (help)CS1 maint: multiple names: authors list (link) - ^ Chernoff, Y. O. (2001). "Mutation processes at the protein level: Is Lamarck back?". Mutation Research. 488 (1): 39–64. doi:10.1016/S1383-5742(00)00060-0. PMID 11223404.
- ^ Wickner RB, Dyda F, Tycko R (2008). "Amyloid of Rnq1p, the basis of the PIN+ prion, has a parallel in-register beta-sheet structure". Proc Natl Acad Sci U S A. 105 (7): 2403–8. doi:10.1073/pnas.0712032105. PMC 2268149. PMID 18268327.
{{cite journal}}: Unknown parameter|month=ignored (help)CS1 maint: multiple names: authors list (link) - ^ Derkatch I. L., Bradley M. E., Zhou P., Chernoff Y. O., Liebman S. W. (1997). "Genetic and Environmental Factors Affecting the de novo Appearance of the [PSI+] Prion in Saccharomyces cerevisiae". Genetics. 147 (2): 507–519. PMC 1208174. PMID 9335589.
{{cite journal}}: CS1 maint: multiple names: authors list (link) - ^ Brown JC, Lindquist S. (2009). "A heritable switch in carbon source utilization driven by an unusual yeast prion". Genes Dev. 23 (19): 2320–32. doi:10.1101/gad.1839109. PMC 2758746. PMID 19797769.
- ^ Rogoza T, Goginashvili A, Rodionova S, Ivanov M, Viktorovskaya O, Rubel A, Volkov K, Mironova L. (2010). "Non-Mendelian determinant [ISP+] in yeast is a nuclear-residing prion form of the global transcriptional regulator Sfp1.". Proc. Natl. Acad. Sci. U.S.A. 107 (23): 10573–7. doi:10.1073/pnas.1005949107. PMC 2890785. PMID 20498075.
{{cite journal}}: CS1 maint: multiple names: authors list (link) - ^ Nemecek J.; et al. (2011). "Retraction for "A prion of yeast metacaspase homolog (Mca1p)detected by a genetic screen"". Proc. Natl. Acad. Sci. U.S.A. url=http://www.pnas.org/content/108/24/10022.2.full.pdf. doi:10.1073/pnas.1107490108.
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