Pernicious Pathogens or Expedient Elements of Inheritance: The Significance of Yeast Prions
نویسندگان
چکیده
Prions are ‘‘infectious’’ misfolded protein states that can template their self-perpetuating conformations onto other molecules of the same type. This unusual folding landscape drives a paradigm-shifting mechanism of inheritance based on changes in protein conformation rather than changes in nucleic acid. The first prion discovered, Prion Protein (PrP), is the causal agent of several human neurodegenerative diseases, including kuru and Creutzfeldt-Jakob [1]. This history has engendered the widespread perception that prions are inherently pathogenic. However, many additional prions have now been found in other eukaryotes in which they influence diverse biological processes and can produce beneficial traits. The most well-characterized of these are found in Saccharomyces cerevisiae and other fungi, such as Podospora anserina [2]. The best-studied prion is the yeast translation termination factor Sup35. In its soluble form, this protein promotes the faithful termination of protein synthesis. However, in its self-perpetuating prion form, known as [PSI], most Sup35 is sequestered into insoluble amyloid fibers. This increases translational readthrough of stop codons and leads to a variety of phenotypic effects [3]. Most of these traits involve multiple loci and arise from previously cryptic genetic variation (e.g., polymorphisms downstream of stop codons) [3]. That is, [PSI] provides access to genetically complex traits in a single step. Sup35 variants from fungi separated by over 100 million years of evolution retain the ability to acquire [PSI] [4,5]. In the laboratory, cells spontaneously acquire [PSI] at low frequencies (,1 in 10) [2,6]. Some have suggested that this element thus provides a ‘‘bet-hedging’’ mechanism, promoting survival by speeding the manifestation of new heritable traits in fluctuating environments [6]. Any population of cells that grows to an appreciable size will include some [PSI] individuals. Although these [PSI] cells are genetically identical to the majority, they will nonetheless express different traits. Even if the phenotypes produced by [PSI] are neutral or detrimental in many environments, a rare strong selective advantage would ensure survival of the population in conditions in which it would otherwise perish [3]. Indeed, population genetics modeling suggests that even extremely rare selective advantages are sufficient to explain the [PSI] switching rates observed in laboratory growth conditions [7]. This line of thinking is intuitively appealing and could easily be extended to other prions. Yet, an opposing view posits that yeast prions are in fact diseases or even artifacts of laboratory culture. A key line of evidence supporting this view had long been the absence of prions in natural yeast isolates that had been tested [8]. However, the recent acquisition of many additional sequenced wild yeast strains has revealed prions’ common presence in nature. Analysis of nearly 700 such strains from diverse ecological niches revealed that many harbored [PSI] and/or other prions [9]. [PSI] was found in ,2% of the strains. [MOT3], which is formed by the Mot3 transcription factor and provides resistance to cellwall toxins, was observed in ,6% of the tested strains [9]. Moreover, one third of the wild strains analyzed had additional phenotypes with the unusual features of prion-based inheritance (e.g., cytoplasmic transmission and strong dependence on the activities of molecular chaperones) [9]. These observations have not eliminated the ‘‘prions as diseases’’ argument (see below), but they clearly demonstrate that prions are not merely an anomaly created in the laboratory. Rather, they play a crucial role in shaping the behavior of natural populations.
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