Life cycle of cytosolic prions

Abstract

Prions are self-templating protein aggregates that were originally identified as the causative agent of prion diseases in mammals, but have since been discovered in other kingdoms. Mammalian prions represent a unique class of infectious agents that are composed of misfolded prion protein. Prion proteins usually exist as soluble proteins but can refold and assemble into highly ordered, self-propagating prion polymers. The prion concept is also applicable to a growing number of non-Mendelian elements of inheritance in lower eukaryotes. While prions identified in mammals are clearly pathogens, prions in lower eukaryotes can be either detrimental or beneficial to the host. Prion phenotypes in fungi are transmitted vertically from mother to daughter cells during cell division and horizontally during mating or abortive mating, but extracellular phases have not been reported. Recent findings now demonstrate that in a mammalian cell environment, protein aggregates derived from yeast prion domains exhibit a prion life cycle similar to mammalian prions propagated ex vivo. This life cycle includes a soluble state of the protein, an induction phase by exogenous prion fibrils, stable replication of prion entities, vertical transmission to progeny and natural horizontal transmission to neighboring cells. Our data reveal that mammalian cells contain all co-factors required for cytosolic prion propagation and dissemination. This has important implications for understanding prion-like properties of disease-related protein aggregates. In light of the growing number of identified functional amyloids, cell-to-cell propagation of cytosolic protein conformers might not only be relevant for the spreading of disease-associated proteins, but might also be of more general relevance under non-disease conditions.

Horizontal Transmission of Cytosolic Sup35 Prions by Extracellular Vesicles

“…In direct coculture experiments, we have previously demonstrated coaggregation of induced NM-GFP aggregates in recipient NM-GFP sol cells with internalized HA-tagged NM from donor NM-HA agg cells ( 26 , 27 ). Of note, coaggregation of microscopically visible donor and recipient NM was a rare event during direct cell contact ( 26 , 27 ), indicating that smaller oligomers might also act as seeds. So far, we did not observe any coaggregation of internalized NM-HA seeds and induced NM-GFP aggregates after the addition of exosomes to recipient cells.…”

“…Cytosolic NM prion induction by direct cell-cell contact depends on the transfer of NM aggregates that seed the aggregation of soluble NM in the recipient cell ( 26 , 27 ). The exact size of the biologically active NM-HA seed is unknown.…”

“…Importantly, NM prions in mammalian cells exhibit infectious properties similar to those of mammalian prions and are horizontally transmitted to bystander cells ( 25 , 26 ). Cell-to-cell contact appears to be most efficient for transmitting the prion phenotype to recipient cells ( 26 , 27 ). In this study, we demonstrate that a fraction of prion infectivity is also secreted in association with extracellular vesicles.…”

Prions on the run: How extracellular vesicles serve as delivery vehicles for self-templating protein aggregates

“…Prions in lower eukaryotes are insoluble, self-perpetuating amyloid-like polymers that act as epigenetic elements of inheritance 9 . Unlike mammalian prions attached at the plasma membrane by a GPI-anchor, yeast prions are predominately cytoplasmic.…”

HSP110 dependent HSP70 disaggregation machinery mediates prion-like propagation of amyloidogenic proteins in metazoa

“…While previous work revealed that metazoan cells exhibit disaggregation activity and also contain all co-factors required for cytosolic propagation and dissemination of an ectopically expressed amyloid-like yeast prion (Cohen et al, 2006; Hofmann and Vorberg, 2013; Hofmann et al, 2013; Krammer et al, 2009a; Krammer et al, 2009b), the nature of these co-factor(s) was still unclear, since direct homologs of HPS104 are absent from the metazoan cytosol. The recent discovery of a metazoan disaggregation machinery in which a particular HSP110-type nucleotide exchange factor (NEF) cooperates with the human HSP70-DNAJ system to fragment and depolymerize amyloid aggregates (Gao et al, 2015; Scior et al, 2018) has raised the question of whether this activity could prevent or promote the prion-like propagation of amyloid-type aggregates in metazoans and what physiological implications this would have.…”