Anti-Prion Systems in Yeast and Inositol Polyphosphates

Abstract

The amyloid-based yeast prions are folded in-register parallel β-sheet polymers. Each prion can exist in a wide array of variants, with different biological properties resulting from different self-propagating amyloid conformations. Yeast has several anti-prion systems, acting in normal cells (without protein overexpression or deficiency). Some anti-prion proteins partially block prion formation (Ssb1,2p, ribosome-associated Hsp70s); others cure a large portion of prion variants that arise [Btn2p, Cur1p, Hsp104 (a disaggregase), Siw14p, and Upf1,2,3p, nonsense-mediated decay proteins], and others prevent prion-induced pathology (Sis1p, essential cytoplasmic Hsp40). Study of the anti-prion activity of Siw14p, a pyrophosphatase specific for 5-diphosphoinositol pentakisphosphate (5PP-IP5), led to the discovery that inositol polyphosphates, signal transduction molecules, are involved in [PSI+] prion propagation. Either inositol hexakisphosphate or 5PP-IP4 (or 5PP-IP5) can supply a function that is needed by nearly all [PSI+] variants. Because yeast prions are informative models for mammalian prion diseases and other amyloidoses, detailed examination of the anti-prion systems, some of which have close mammalian homologues, will be important for the development of therapeutic measures.

Three J-proteins impact Hsp104-mediated variant-specific prion elimination: a new critical role for a low-complexity domain

“…It is worth noting that Sis1 orthologs have retained the ability to propagate some variants of [PSI + ] and [RNQ + ], but all higher eukaryotic orthologs examined to date lack the ability to substitute for Sis1 in Hsp104-mediated curing, now including human Hdj1 (Sporn and Hines 2015), D. melanogaster Droj1 (Astor et al 2018), A. thaliana atDjB1 (Verma et al 2017), and five other A. thaliana Sis1 orthologs (Sahi and Hines, unpublished observations). Wickner et al, have described Hsp104-mediated curing as one of many "anti-prion" functions of yeast (Wickner et al 2015(Wickner et al , 2018. One interpretation of these findings, in that light, might be that these orthologs have retained some prion-maintaining functions but have intriguingly lost this "anti-prion" function.…”

“…Hsp70 then recruits Hsp104, the chaperone responsible for the physical severing of amyloid fibrils (Cox et al 2003;Aron et al 2007;Higurashi et al 2008;Tipton et al 2008;Winkler et al 2012;Harris et al 2014). Hsp104, which plays a critical role in the solubilization of stress-induced protein aggregates (Wendler et al 2009;Yokom et al 2017), is necessary for the propagation of all known amyloid-based prions (Wickner et al 2018). Hsp104 threads prion monomers from amyloid cores through its central cavity, solubilizing them and eventually remodeling and ultimately fragmenting the amyloid aggregates to generate new propagons-the unit of proteinaceous infection particles that must be propagated to maintain the Communicated by M. Kupiec.…”

The Pub1 and Upf1 Proteins Act in Concert to Protect Yeast from Toxicity of the [<em>PSI</em>⁺] Prion

“…and Arg82, enzymes involved in the inositol polyphosphate biosynthetic pathway [21]. Mechanisms of action of these proteins remains elusive, with an exception of PrA and PrB proteases, which cleave off an important part of the Sup35 prion-forming domain.…”

Recent Insights on Alzheimer’s Disease Originating from Yeast Models

“…Besides these disease-causing prions, a plethora of prions with mostly unknown function has been discovered also in yeast [ 212 , 213 ]. Except for Podospora anserina ’s [Het-s] prion, most functions of all these prions are unclear and all are toxic, or at least growth-inhibitory, but still are supposed to be beneficial for the survival of cells under stress conditions [ 214 , 215 , 216 ]. To ensure optimal survival but limit malicious effects, prion formation has to be tightly controlled and carefully balanced.…”