Prions, Chaperones, and Proteostasis in Yeast

Abstract

Prions are alternatively folded, self-perpetuating protein isoforms involved in a variety of biological and pathological processes. Yeast prions are protein-based heritable elements that serve as an excellent experimental system for studying prion biology. The propagation of yeast prions is controlled by the same Hsp104/70/40 chaperone machinery that is involved in the protection of yeast cells against proteotoxic stress. Ribosome-associated chaperones, proteolytic pathways, cellular quality-control compartments, and cytoskeletal networks influence prion formation, maintenance, and toxicity. Environmental stresses lead to asymmetric prion distribution in cell divisions. Chaperones and cytoskeletal proteins mediate this effect. Overall, this is an intimate relationship with the protein quality-control machinery of the cell, which enables prions to be maintained and reproduced. The presence of many of these same mechanisms in higher eukaryotes has implications for the diagnosis and treatment of mammalian amyloid diseases.

Figure 1.

Role of chaperones in the propagation of the Sup35 prion. (A) Polymer fragmentation and propagon formation at the normal levels of Hsp104, Hsp70, and Hsp40 proteins. (B) Impairment of prion propagation in the absence of Hsp104. (C) Impairment of prion propagation at high levels of Hsp104 (two models are shown). (Red square) Sup35N (PrD) in prion form; (red line) Sup35M linker and Sup35N in a misfolded intermediate form; (red spiral line) Sup35NM region in a nonprion form; (red circle) globular Sup35C domain.

Figure 2.

Model for the effects of ribosome-associated chaperones in prion formation and propagation. (A) Wild-type cell. (B) Cell lacking Ssb. (C) Cell lacking Zuo1 and/or Ssz1. Sup35 regions and isoforms are shown as in Figure 1. The cytosolic Hsp40 protein is not shown for simplicity.

Figure 3.

Model for the role of the actin cytoskeleton in the formation of the Sup35 prion. (A) Initial assembly of misfolded Sup35 in the peripheral cytoskeletal sites. (B) Cytoskeleton-mediated accumulation of Sup35 in the quality-control compartment, followed by conversion into a prion form. Sup35 regions and isoforms are shown as in Figure 1.

Figure 4.

Model for prion destabilization after HS. (Top) Dynamics of Hsp104, Hsp70-Ssa, actin assembly protein Lsb2, and cytosolic-processed isoform (Lsb1′) of its paralog Lsb1 during short-term (acute) and prolonged (chronic) temperature stress. (Bottom) Asymmetric segregation of prions, heat-shock damaged proteins, and chaperones in cell division after stress. Sup35 regions and isoforms are shown as in Figure 1.