Chaperone-dependent amyloid assembly protects cells from prion toxicity

Peter M. Douglas, Sebastian Treusch, Hong Yu Ren, Randal Halfmann, Martin L. Duennwald, Susan Lindquist, Douglas M. Cyr

Research output: Contribution to journalArticle

119 Citations (Scopus)

Abstract

Protein conformational diseases are associated with the aberrant accumulation of amyloid protein aggregates, but whether amyloid formation is cytotoxic or protective is unclear. To address this issue, we investigated a normally benign amyloid formed by the yeast prion [RNQ+]. Surprisingly, modest overexpression of Rnq1 protein was deadly, but only when preexisting Rnq1 was in the [RNQ+] prion conformation. Molecular chaperones protect against protein aggregation diseases and are generally believed to do so by solubilizing their substrates. The Hsp40 chaperone, Sis1, suppressed Rnq1 proteotoxicity, but instead of blocking Rnq1 protein aggregation, it stimulated conversion of soluble Rnq1 to [RNQ+] amyloid. Furthermore, interference with Sis1-mediated [RNQ+] amyloid formation exacerbated Rnq1 toxicity. These and other data establish that even subtle changes in the folding homeostasis of an amyloidogenic protein can create a severe proteotoxic gain-of-function phenotype and that chaperone-mediated amyloid assembly can be cytoprotective. The possible relevance of these findings to other phenomena, including prion-driven neurodegenerative diseases and heterokaryon incompatibility in fungi, is discussed.

Original languageEnglish (US)
Pages (from-to)7206-7211
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume105
Issue number20
DOIs
StatePublished - May 20 2008

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Prions
Amyloid
Amyloidogenic Proteins
Proteins
Molecular Chaperones
Neurodegenerative Diseases
Homeostasis
Fungi
Yeasts
Phenotype

Keywords

  • Hsp40
  • Neurodegenerative disease
  • Rnq1
  • Sis1
  • Yeast prion

ASJC Scopus subject areas

  • Genetics
  • General

Cite this

Chaperone-dependent amyloid assembly protects cells from prion toxicity. / Douglas, Peter M.; Treusch, Sebastian; Ren, Hong Yu; Halfmann, Randal; Duennwald, Martin L.; Lindquist, Susan; Cyr, Douglas M.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 105, No. 20, 20.05.2008, p. 7206-7211.

Research output: Contribution to journalArticle

Douglas, Peter M. ; Treusch, Sebastian ; Ren, Hong Yu ; Halfmann, Randal ; Duennwald, Martin L. ; Lindquist, Susan ; Cyr, Douglas M. / Chaperone-dependent amyloid assembly protects cells from prion toxicity. In: Proceedings of the National Academy of Sciences of the United States of America. 2008 ; Vol. 105, No. 20. pp. 7206-7211.
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