{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,12]],"date-time":"2025-10-12T04:48:32Z","timestamp":1760244512628,"version":"build-2065373602"},"reference-count":45,"publisher":"MDPI AG","issue":"12","license":[{"start":{"date-parts":[[2022,12,18]],"date-time":"2022-12-18T00:00:00Z","timestamp":1671321600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Intramural Program of the National Institutes of Health","award":["ZIA DK024946-24"],"award-info":[{"award-number":["ZIA DK024946-24"]}]},{"name":"National Institute of Diabetes, and Digestive and Kidney Diseases","award":["ZIA DK024946-24"],"award-info":[{"award-number":["ZIA DK024946-24"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Biology"],"abstract":"<jats:p>Human J-domain protein (JDP) DnaJB6 has a broad and potent activity that prevents formation of amyloid by polypeptides such as polyglutamine, A-beta, and alpha-synuclein, related to Huntington\u2019s, Alzheimer\u2019s, and Parkinson\u2019s diseases, respectively. In yeast, amyloid-based [PSI+] prions, which rely on the related JDP Sis1 for replication, have a latent toxicity that is exposed by reducing Sis1 function. Anti-amyloid activity of DnaJB6 is very effective against weak [PSI+] prions and the Sup35 amyloid that composes them, but ineffective against strong [PSI+] prions composed of structurally different amyloid of the same Sup35. This difference reveals limitations of DnaJB6 that have implications regarding its therapeutic use for amyloid disease. Here, we find that when Sis1 function is reduced, DnaJB6 represses toxicity of strong [PSI+] prions and inhibits their propagation. Both Sis1 and DnaJB6, which are regulators of protein chaperone Hsp70, counteract the toxicity by reducing excessive incorporation of the essential Sup35 into prion aggregates. However, while Sis1 apparently requires interaction with Hsp70 to detoxify [PSI+], DnaJB6 counteracts prion toxicity by a different, Hsp70-independent mechanism.<\/jats:p>","DOI":"10.3390\/biology11121846","type":"journal-article","created":{"date-parts":[[2022,12,19]],"date-time":"2022-12-19T05:55:43Z","timestamp":1671429343000},"page":"1846","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Human J-Domain Protein DnaJB6 Protects Yeast from [PSI+] Prion Toxicity"],"prefix":"10.3390","volume":"11","author":[{"suffix":"III","given":"Richard E.","family":"Dolder","sequence":"first","affiliation":[{"name":"Laboratory of Biochemistry and Genetics, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jyotsna","family":"Kumar","sequence":"additional","affiliation":[{"name":"Department of Chemistry, University of Connecticut, Storrs, CT 06269, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Michael","family":"Reidy","sequence":"additional","affiliation":[{"name":"Laboratory of Biochemistry and Genetics, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Daniel C.","family":"Masison","sequence":"additional","affiliation":[{"name":"Laboratory of Biochemistry and Genetics, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2022,12,18]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"566","DOI":"10.1126\/science.7909170","article-title":"[URE3] as an altered ure2 protein: Evidence for a prion analog in Saccharomyces Cerevisiae","volume":"264","author":"Wickner","year":"1994","journal-title":"Science"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"323","DOI":"10.1038\/nature02392","article-title":"Conformational variations in an infectious protein determine prion strain differences","volume":"428","author":"Tanaka","year":"2004","journal-title":"Nature"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"559","DOI":"10.1093\/genetics\/156.2.559","article-title":"A role for cytosolic hsp70 in yeast [PSI+] prion propagation and [PSI+] as a cellular stress","volume":"156","author":"Jung","year":"2000","journal-title":"Genetics"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"6236","DOI":"10.1093\/emboj\/20.22.6236","article-title":"Strains of [PSI+] are distinguished by their efficiencies of prion-mediated conformational conversion","volume":"20","author":"Uptain","year":"2001","journal-title":"EMBO J."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"880","DOI":"10.1126\/science.7754373","article-title":"Role of the chaperone protein hsp104 in propagation of the yeast prion-like factor [psi+]","volume":"268","author":"Chernoff","year":"1995","journal-title":"Science"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"185","DOI":"10.1534\/genetics.112.142307","article-title":"Prokaryotic chaperones support yeast prions and thermotolerance and define disaggregation machinery interactions","volume":"192","author":"Reidy","year":"2012","journal-title":"Genetics"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"623","DOI":"10.1083\/jcb.114.4.623","article-title":"Characterization of Sis1, a Saccharomyces cerevisiae homologue of bacterial dnaj proteins","volume":"114","author":"Luke","year":"1991","journal-title":"J. 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