Prions, protein homeostasis, and phenotypic diversity

Prions are fascinating but often misunderstood protein aggregation phenomena. The traditional association of the mammalian prion protein with disease has overshadowed a potentially more interesting attribute of prions: their ability to create protein-based molecular memories. In fungi, prions alter the relationship between genotype and phenotype in a heritable way that diversifies clonal populations. Recent findings in yeast indicate that prions might be much more common than previously realized. Moreover, prion-driven phenotypic diversity increases under stress, and can be amplified by the dynamic maturation of prion-initiating states. In this article, we suggest that these qualities allow prions to act as ‘bet-hedging’ devices that facilitate the adaptation of yeasts to stressful environments, and might speed the evolution of new traits.

Introduction

Prions are self-replicating protein entities that underlie the spread of a mammalian neurodegenerative disease, variously known as kuru, scrapie and bovine spongiform encephalopathy, in humans, sheep and cows, respectively [1]. However, most prions have been discovered in lower organisms and in particular, the yeast Saccharomyces cerevisiae. Despite assertions that these prions, too, are disease-causing agents [2] (Box 1), many lines of evidence suggest that these mysterious elements are generally benign and, in fact, in some cases beneficial. In fungi, prions act as epigenetic elements that increase phenotypic diversity in a heritable way and can also increase survival in diverse environmental conditions 3, 4, 5, 6. In higher organisms, prions might even be a mechanism to maintain long-term physiological states, as suggested for the Aplysia californica (sea slug) neuronal isoform of cytoplasmic polyadenylation element binding protein (CPEB). The prion form of this protein appears to be responsible for creating stable synapses in the brain [7]. CPEB is the prominent first example of what might be a large group of prion-like physiological switches, the potential scope of which cannot be given adequate coverage here. Instead, this article will focus on prions as protein-based genetic elements, on their ability to drive reversible switching in diverse phenotypes and on the way that such switching can promote the evolution of phenotypic novelty.

The self-templating replicative state of most biochemically characterized prions is amyloid 5, 8 (Figure 1), although other types of self-propagating protein conformations might also give rise to prion phenomena 9, 10. Amyloid is a highly ordered, fibrillar protein aggregate with a unique set of biophysical characteristics that facilitate prion propagation: extreme stability, assembly by nucleated polymerization and a high degree of templating specificity. Prion propagation proceeds from a single nucleating event that occurs within an otherwise stable intracellular population of non-prion conformers. The nucleus then elongates into a fibrillar species by acting as a template for the conformational conversion of non-prion conformers 11, 12 (Figure 1). Finally, the growing protein fiber fragments into smaller propagating entities, which are ultimately disseminated to daughter cells [6]. Because the change in protein conformation causes a change in function, these self-perpetuating conformational changes create heritable phenotypes unique to the determinant protein and its genetic background (Figure 1). The genetic properties that arise are distinct from those of most nuclear-encoded mutations: prion phenotypes are dominant in genetic crosses and exhibit non-mendelian inheritance patterns. Hence prion-based genetic elements are denoted with capital letters and brackets: [PRION].

Protein remodeling factors, chaperones and other protein quality-control mechanisms interact with prions at every step in their propagation. Further, prion-driven phenotypic switches are modulated by environmental conditions that perturb protein homeostasis: [13] the proteome-wide balance of protein synthesis, folding, trafficking and degradation processes [14]. Prions could thereby constitute an intrinsic part of the biological response to stress. We postulate that the relationship between prions and protein homeostasis, and the dynamic nature of prion propagation, render prions as sophisticated evolutionary ‘bet-hedging’ devices (a risk aversion strategy). In this report, we explore several intriguing features of prion biology that together argue for a general role for prions in adaptation to new environments and thereby the evolution of new traits.