Physiological and environmental control of yeast prions

Abstract

Prions are self-perpetuating protein isoforms that cause fatal and incurable neurodegenerative disease in mammals. Recent evidence indicates that a majority of human proteins involved in amyloid and neural inclusion disorders possess at least some prion properties. In lower eukaryotes, such as yeast, prions act as epigenetic elements, which increase phenotypic diversity by altering a range of cellular processes. While some yeast prions are clearly pathogenic, it is also postulated that prion formation could be beneficial in variable environmental conditions. Yeast and mammalian prions have similar molecular properties. Crucial cellular factors and conditions influencing prion formation and propagation were uncovered in the yeast models. Stress-related chaperones, protein quality control deposits, degradation pathways and cytoskeletal networks control prion formation and propagation in yeast. Environmental stresses trigger prion formation and loss, supposedly acting via influencing intracellular concentrations of the prion-inducing proteins, and/or by localizing prionogenic proteins to the prion induction sites via heterologous ancillary helpers. Physiological and environmental modulation of yeast prions points to new opportunities for pharmacological intervention and/or prophylactic measures targeting general cellular systems rather than the properties of individual amyloids and prions.

Stress-dependent Proteolytic Processing of the Actin Assembly Protein Lsb1 Modulates a Yeast Prion

“…However, other data point to the involvement of targeted cytoskeleton-dependent aggregate retention and/or retrograde transport (10,14) Notably, the yeast prion [PSI ϩ ] is also asymmetrically distributed in the cell divisions after stress, and this asymmetric distribution is chaperone-dependent (21). The actin cytoskeleton is also involved in [PSI ϩ ] maintenance (4,22). This makes [PSI ϩ ] a powerful system for investigation of the mechanisms dealing with aggregated proteins during and after stresses.…”

“…Environmental stresses such as heat shock (HS) lead to an increased misfolding of a wide range of proteins (1)(2)(3)(4). Recent data suggest that the spread of large quantities of misfolded proteins throughout the cell could be toxic, whereas their assembly into the large aggregate deposits plays, to a certain extent, a protective role (5)(6)(7)(8).…”

“…The human Wiskott-Aldrich syndrome protein and its yeast homolog Las17 are the crucial components (23). The activity of Las17 is regulated by multiple interacting partners that bind to its proline-rich regions via SH3 4 domains and form dynamic protein complexes at actin patches, major sites of endocytic vesicle assembly. Regulation of these complexes by altered protein-protein interaction and protein turnover involves ubiquitination by the HECT-type ubiquitin ligase Rsp5, and/or binding to ubiquitin (Ub) (24).…”

Linking RNA Dysfunction and Neurodegeneration in Amyotrophic Lateral Sclerosis

“…Similar domains are characteristic of yeast prions that reversibly change their conformation, selfaggregate, and propagate this conformation onto natively folded proteins [88]. Prion-like domains are also found in mammalian proteins whose function requires reversible selfaggregation, including proteins that are involved in the formation of stress granules [89], RNA-dense cytoplasmic particles that sequester nonessential mRNAs and prevent their translation when cells are under duress [90].…”

Are there prions in plants?

“…Modern studies of yeast and fungal prions confirm that protein conformations (that is, alterations of cellular components that are distinct from the DNAbased chromosomal genes) can control certain heritable traits (4). Sadly, instead of becoming early pioneers of nonconventional mechanisms of inheritance, Lysenko and his followers chose to spread their views by administrative means, eventually losing the scientific contents of these views in the process.…”