How Do Yeast Cells Contend with Prions?

Abstract

<jats:p>Infectious proteins (prions) include an array of human (mammalian) and yeast amyloid diseases in which a protein or peptide forms a linear β-sheet-rich filament, at least one functional amyloid prion, and two functional infectious proteins unrelated to amyloid. In Saccharomyces cerevisiae, at least eight anti-prion systems deal with pathogenic amyloid yeast prions by (1) blocking their generation (Ssb1,2, Ssz1, Zuo1), (2) curing most variants as they arise (Btn2, Cur1, Hsp104, Upf1,2,3, Siw14), and (3) limiting the pathogenicity of variants that do arise and propagate (Sis1, Lug1). Known mechanisms include facilitating proper folding of the prion protein (Ssb1,2, Ssz1, Zuo1), producing highly asymmetric segregation of prion filaments in mitosis (Btn2, Hsp104), competing with the amyloid filaments for prion protein monomers (Upf1,2,3), and regulation of levels of inositol polyphosphates (Siw14). It is hoped that the discovery of yeast anti-prion systems and elucidation of their mechanisms will facilitate finding analogous or homologous systems in humans, whose manipulation may be useful in treatment.</jats:p>

From Seeds to Fibrils and Back: Fragmentation as an Overlooked Step in the Propagation of Prions and Prion-Like Proteins

“…The biology of yeast prions has recently been reviewed elsewhere [ 40 , 41 , 42 , 43 ]. Hence, we will limit our discussion to the role of fragmentation in yeast prion propagation.…”

Extracellular Vesicles-Encapsulated Yeast Prions and What They Can Tell Us about the Physical Nature of Propagons

“…Hence, that an individual yeast cell contains a defined number of propagons in equilibrium with both monomers and larger aggregates, some of which are passively transmitted to the emerging bud, does not quite add up with these antiaging protecting mechanisms [ 10 , 64 , 65 , 66 ]. Because propagons contain the structural information required to propagate the prion conformation, they should be recognized as misfolded abnormal species by antiprion systems and either cleared or addressed to protein inclusion sites [ 10 , 64 , 65 , 66 ]. Due to their high numbers and small sizes, propagons may escape quality control mechanisms and diffuse through the mother–bud junction despite crowding.…”

“…Intrinsic properties of each prion variant, the genetic background of the yeast strains carrying the prions, as well as metabolic and environmental factors affect the transmission of propagons [ 18 , 19 , 53 , 68 , 69 , 70 , 90 ]. As discussed above, because of overlapping protein quality control, antiprion and antiaging systems, prion loss is expected to occur, albeit at low frequencies at each cell division, particularly in young cells [ 10 , 64 , 65 , 66 ]. However, the mitotic stabilities of several [ PSI + ], [ URE3 ] or [ PIN + ] variants are on par with those of chromosomes or centromere plasmids: even after extended cultivation periods or hundreds of generations, prion-free cells or sectored colonies seldom appear.…”

“…Over the past few decades, many prions have been described in the yeast Saccharomyces cerevisiae ( Table 1 ). [ PSI + ], [ URE3 ] and [ PIN + ], which correspond to the prion forms of Sup35p, Ure2p and Rnq1p, respectively, are the most extensively studied (reviewed in [ 6 , 7 , 8 , 9 , 10 ]). A common feature shared by most of these prion proteins is their ability to assemble into highly ordered self-replicating β-rich aggregates, most often of an amyloid nature [ 6 , 7 , 10 ].…”

“…The large conformational landscape of prion proteins leads to the formation of distinct strains with different seeding propensities and prion phenotypes ( Figure 1 ) [ 16 , 17 , 18 , 19 ]. These high-molecular prion assemblies are dynamic and are engaged and remodeled by molecular chaperones (e.g., Hsp104, Hsp70, Hsp40), proteolytic systems and other components of the protein quality control machinery ( Figure 1 ) (reviewed in [ 7 , 8 , 10 , 20 ]).…”