Anti-Prion Systems Block Prion Transmission, Attenuate Prion Generation, Cure Most Prions as They Arise and Limit Prion-Induced Pathology in Saccharomyces cerevisiae

SIMPLE SUMMARY: Virus and bacterial infections are opposed by their hosts at many levels. Similarly, we find that infectious proteins (prions) are severely restricted by an array of host systems, acting independently to prevent infection, generation, propagation and the ill effects of yeast prions. These ‘anti-prion systems’ work in normal cells without the overproduction or deficiency of any components. DNA repair systems reverse the effects of DNA damage, with only a rare lesion propagated as a mutation. Similarly, the combined effects of several anti-prion systems cure and block the generation of all but 1 in about 5000 prions arising. We expect that application of our approach to mammalian cells will detect analogous or even homologous systems that will be useful in devising therapy for human amyloidoses, most of which are prions. ABSTRACT: All variants of the yeast prions [PSI+] and [URE3] are detrimental to their hosts, as shown by the dramatic slowing of growth (or even lethality) of a majority, by the rare occurrence in wild isolates of even the mildest variants and by the absence of reproducible benefits of these prions. To deal with the prion problem, the host has evolved an array of anti-prion systems, acting in normal cells (without overproduction or deficiency of any component) to block prion transmission from other cells, to lower the rates of spontaneous prion generation, to cure most prions as they arise and to limit the damage caused by those variants that manage to elude these (necessarily) imperfect defenses. Here we review the properties of prion protein sequence polymorphisms Btn2, Cur1, Hsp104, Upf1,2,3, ribosome-associated chaperones, inositol polyphosphates, Sis1 and Lug1, which are responsible for these anti-prion effects. We recently showed that the combined action of ribosome-associated chaperones, nonsense-mediated decay factors and the Hsp104 disaggregase lower the frequency of [PSI+] appearance as much as 5000-fold. Moreover, while Btn2 and Cur1 are anti-prion factors against [URE3] and an unrelated artificial prion, they promote [PSI+] prion generation and propagation.