Abstract
ABSTRACTPrions are infectious protein particles that replicate by templating their aggregated state onto soluble protein of the same type. Originally identified as the causative agent of transmissible spongiform encephalopathies, prions in yeast (Saccharomyces cerevisiae) are epigenetic elements of inheritance that induce phenotypic changes of their host cells. The prototype yeast prion is the translation termination factor Sup35. Prions composed of Sup35 or its modular prion domain NM are heritable and are transmitted vertically to progeny or horizontally during mating. Interestingly, in mammalian cells, protein aggregates derived from yeast Sup35 NM behave as true infectious entities that employ dissemination strategies similar to those of mammalian prions. While transmission is most efficient when cells are in direct contact, we demonstrate here that cytosolic Sup35 NM prions are also released into the extracellular space in association with nanometer-sized membrane vesicles. Importantly, extracellular vesicles are biologically active and are taken up by recipient cells, where they induce self-sustained Sup35 NM protein aggregation. Thus, in mammalian cells, extracellular vesicles can serve as dissemination vehicles for protein-based epigenetic information transfer.
Highlights
Prions are self-perpetuating proteinaceous elements that encipher phenotypic information in the absence of coding nucleic acid
We have previously shown that Sup35 NM prions can be efficiently induced by coculture of mouse N2a donor cells harboring hemagglutinin (HA)-tagged NM prions (NM-HAagg) with recipient cells expressing soluble NM-green fluorescent protein (NMGFPsol) [26]
Induction depended on the transmission of NMHAagg seeds from donor to bystander recipient cells and was most efficient when cells were cultured in close proximity, strongly suggesting that direct cellular contact is the most effective route of cytosolic prion dissemination
Summary
Prions are self-perpetuating proteinaceous elements that encipher phenotypic information in the absence of coding nucleic acid. 1% of the human proteome contains lowcomplexity domains enriched in asparagine and glutamine residues with compositional similarity to yeast prion domains [14]. Many of those human proteins form functional RNA-protein complexes, and their prion-like domains are critical for the rapid self-assembly of these complexes under stressful conditions [24]. The NM domain of Sup shows no sequence homology with mammalian proteins and allows us to study prion formation without the adverse effects of any loss of function. Mammalian cells can package protein assemblies with yeast prion domains into secreted vesicles that transmit the aggregation state to bystander cells. In light of the high number of mammalian proteins harboring lowcomplexity domains with compositional similarity to those of yeast prions, it is tempting to speculate that dissemination of prion-like protein assemblies could play a more general role in cell-cell communication
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