Rebels with a cause: molecular features and physiological consequences of yeast prions

Abstract

Prions are proteins that convert between structurally and functionally distinct states, at least one of which is self-perpetuating. The prion fold templates the conversion of native protein, altering its structure and function, and thus serves as a protein-based element of inheritance. Molecular chaperones ensure that these prion aggregates are divided and faithfully passed from mother cells to their daughters. Prions were originally identified as the cause of several rare neurodegenerative diseases in mammals, but the last decade has brought great progress in understanding their broad importance in biology and evolution. Most prion proteins regulate information flow in signaling networks, or otherwise affect gene expression. Consequently, switching into and out of prion states creates diverse new traits – heritable changes based on protein structure rather than nucleic acid. Despite intense study of the molecular mechanisms of this paradigm-shifting, epigenetic mode of inheritance, many key questions remain. Recent studies in yeast that support the view that prions are common, often beneficial elements of inheritance that link environmental stress to the appearance of new traits.

Prion-like domains as epigenetic regulators, scaffolds for subcellular organization, and drivers of neurodegenerative disease

“…The beneficial phenotypes conferred by yeast prions are often observed under stress conditions, which has led to the suggestion that yeast prions constitute bet-hedging devices, which can reveal potentially adaptive genetic diversity in fluctuating environments (Du et al, 2015; Garcia and Jarosz, 2014; Halfmann et al, 2010; Halfmann and Lindquist, 2010; Masel and Bergman, 2003; Newby and Lindquist, 2013; Tyedmers et al, 2008). This process is facilitated by the conformational range of PrDs, which can access multiple, distinct cross-β structures or strains (Shorter, 2010).…”

“…However, several of the advantageous [ PSI + ]-dependent phenotypes of wild yeast strains were not replicated in another study (Wickner et al, 2015). Nonetheless, the preponderance of evidence suggests that yeast prion proteins undergo environmentally-sensitive, alternative folding to effect epigenetic changes that increase fitness in response to fluctuating environments (Garcia and Jarosz, 2014; Halfmann et al, 2012; Newby and Lindquist, 2013; Suzuki et al, 2012). …”

Engineering enhanced protein disaggregases for neurodegenerative disease

“…65,66,172,173 Moreover, Hsp104 activity is also likely adapted to propagate various beneficial yeast prions. 31,33,34,41,46,90 With regard to these 2 important activities, the potentiated Hsp104 variants uncovered in our screen display deficits. ], which would in turn inhibit revelation of cryptic variation and rapid evolution of new traits in response to environmental stress.…”

“…], which would in turn inhibit revelation of cryptic variation and rapid evolution of new traits in response to environmental stress. 32,33,35,41,45,46 These 2 differences between WT Hsp104 and potentiated Hsp104 in yeast likely explain why the potentiated forms were not fixed during evolution.…”

“…[31][32][33][34][35][36][37][38][39][40][41][42][43][44][45][46] For example, the same type of prion domain that enables Sup35 and Mot3 to form beneficial prions in yeast 31,33,41 causes TDP-43 and FUS to misfold in ALS, 2,47-51 and hnRNPA1 and hnRNPA2 to misfold in multisystem proteinopathy. 52,53 Indeed, yeast exploit prions for beneficial purposes, including stress resistance and the evolution of new traits in fluctuating environments.…”