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Here, we trace the history of these prions and describe the array of anti\u2010prion systems in <jats:styled-content style=\"fixed-case\"><jats:italic>S. cerevisiae<\/jats:italic><\/jats:styled-content>. These systems work together to block prion infection, prion generation, prion propagation, prion segregation, and the lethal (and near\u2010lethal) effects of most variants of these prions. Each system lowers the appearance of prions 2\u2010 to 15\u2010fold, but together, ribosome\u2010associated chaperones, the Hsp104 disaggregase, and the Sup35p\u2010binding Upf proteins lower the frequency of [PSI+] appearance by ~5000\u2010fold. [PSI+] variants can be categorized by their sensitivity to the various anti\u2010prion systems, with the majority of prion isolates sensitive to all three of the above\u2010mentioned systems. Yeast prions have been used to screen for human anti\u2010prion proteins, and five of the Bag protein family members each have such activity. We suggest that manipulation of human anti\u2010prion systems may be useful in preventing or treating some of the many human amyloidoses currently found to be prions with the same amyloid architecture as the yeast prions.<jats:boxed-text content-type=\"graphic\" position=\"anchor\"><jats:graphic xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" mimetype=\"image\/png\" position=\"anchor\" specific-use=\"enlarged-web-image\" xlink:href=\"graphic\/jnc70045-fig-0006-m.png\"><jats:alt-text>image<\/jats:alt-text><\/jats:graphic><\/jats:boxed-text><\/jats:p>","DOI":"10.1111\/jnc.70045","type":"journal-article","created":{"date-parts":[[2025,3,27]],"date-time":"2025-03-27T06:34:49Z","timestamp":1743057289000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Anti\u2010Prion Systems in <scp><i>Saccharomyces cerevisiae<\/i><\/scp>"],"prefix":"10.1111","volume":"169","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0273-8247","authenticated-orcid":false,"given":"Reed B.","family":"Wickner","sequence":"first","affiliation":[{"name":"Laboratory of Biochemistry and Genetics National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health  Bethesda Maryland USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuho","family":"Hayashi","sequence":"additional","affiliation":[{"name":"Laboratory of Biochemistry and Genetics National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health  Bethesda Maryland USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Herman K.","family":"Edskes","sequence":"additional","affiliation":[{"name":"Laboratory of Biochemistry and Genetics National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health  Bethesda Maryland USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2025,3,25]]},"reference":[{"key":"e_1_2_24_2_1","doi-asserted-by":"publisher","DOI":"10.1007\/BF00341717"},{"key":"e_1_2_24_3_1","doi-asserted-by":"publisher","DOI":"10.1038\/214764a0"},{"key":"e_1_2_24_4_1","doi-asserted-by":"publisher","DOI":"10.1016\/0006-291X(66)90478-5"},{"key":"e_1_2_24_5_1","doi-asserted-by":"publisher","DOI":"10.1080\/19336896.2015.1022022"},{"key":"e_1_2_24_6_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.230315097"},{"key":"e_1_2_24_7_1","doi-asserted-by":"publisher","DOI":"10.1038\/nbt855"},{"key":"e_1_2_24_8_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0006-3495(02)75244-2"},{"key":"e_1_2_24_9_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41591-023-02729-2"},{"key":"e_1_2_24_10_1","doi-asserted-by":"publisher","DOI":"10.1111\/mmi.13697"},{"key":"e_1_2_24_11_1","doi-asserted-by":"publisher","DOI":"10.1146\/annurev.micro.60.080805.142106"},{"key":"e_1_2_24_12_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pgen.1003257"},{"key":"e_1_2_24_13_1","doi-asserted-by":"publisher","DOI":"10.1534\/genetics.111.136655"},{"key":"e_1_2_24_14_1","doi-asserted-by":"crossref","first-page":"3449","DOI":"10.1091\/mbc.e03-01-0007","article-title":"Conservation of the Prion Properties of Ure2p Through Evolution","volume":"14","author":"Baudin\u2010Baillieu A.","year":"2003","journal-title":"Molecular Biology of the Cell"},{"key":"e_1_2_24_15_1","doi-asserted-by":"publisher","DOI":"10.1021\/bi700826b"},{"key":"e_1_2_24_16_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.95.23.13407"},{"key":"e_1_2_24_17_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00294-019-01006-5"},{"key":"e_1_2_24_18_1","doi-asserted-by":"publisher","DOI":"10.1128\/jvi.66.4.2096-2101.1992"},{"key":"e_1_2_24_19_1","doi-asserted-by":"publisher","DOI":"10.1093\/genetics\/iyab1013"},{"key":"e_1_2_24_20_1","doi-asserted-by":"publisher","DOI":"10.1038\/srep32117"},{"key":"e_1_2_24_21_1","doi-asserted-by":"publisher","DOI":"10.1038\/sj.emboj.7600772"},{"key":"e_1_2_24_22_1","doi-asserted-by":"publisher","DOI":"10.1038\/379339a0"},{"key":"e_1_2_24_23_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2016.09.017"},{"key":"e_1_2_24_24_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.molcel.2019.10.028"},{"key":"e_1_2_24_25_1","doi-asserted-by":"publisher","DOI":"10.1021\/bi050724t"},{"key":"e_1_2_24_26_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0611158104"},{"key":"e_1_2_24_27_1","doi-asserted-by":"publisher","DOI":"10.1007\/BF00351802"},{"key":"e_1_2_24_28_1","doi-asserted-by":"publisher","DOI":"10.1046\/j.1365-2958.2000.01761.x"},{"key":"e_1_2_24_29_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.7754373"},{"key":"e_1_2_24_30_1","doi-asserted-by":"publisher","DOI":"10.1128\/MCB.19.12.8103"},{"key":"e_1_2_24_31_1","first-page":"101","volume-title":"Protein Synthesis and Targeting in Yeast","author":"Chernoff Y. 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