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PNAS 97 (12): 6625-6629

Copyright © 2000 by the National Academy of Sciences.

BIOLOGICAL SCIENCES / GENETICS

A protein required for prion generation: [URE3] induction requires the Ras-regulated Mks1 protein

Herman K. Edskes Reed B. Wickner*

Laboratory of Biochemistry and Genetics, National Institute of Diabetes, Digestive and Kidney Diseases, National Institutes of Health, Building 8, Room 225, 8 Center Drive, MSC 0830, Bethesda, MD 20892-0830

Accepted for publication April 13, 2000.

Received for publication March 23, 2000.

Abstract: Infectious proteins (prions) can arise de novo as well as by transmission from another individual. De novo prion generation is believed responsible for most cases of Creutzfeldt–Jakob disease and for initiating the mad cow disease epidemic. However, the cellular components needed for prion generation have not been identified in any system. The [URE3] prion of Saccharomyces cerevisiae is an infectious form of Ure2p, apparently a self-propagating amyloid. We now demonstrate a protein required for de novo prion generation. Mks1p negatively regulates Ure2p and is itself negatively regulated by the presence of ammonia and by the Ras–cAMP pathway. We find that in mks1{Delta} strains, de novo generation of the [URE3] prion is blocked, although [URE3] introduced from another strain is expressed and propagates stably. Ras2Val19 increases cAMP production and also blocks [URE3] generation. These results emphasize the distinction between prion generation and propagation, and they show that cellular regulatory mechanisms can critically affect prion generation.

* To whom reprint requests should be addressed. E-mail: wickner{at}helix.nih.gov.

Communicated by Herbert Tabor, National Institutes of Health, Bethesda, MD

Article published online before print: Proc. Natl. Acad. Sci. USA, 10.1073/pnas.120168697.

Article and publication date are at www.pnas.org/cgi/doi/10.1073/pnas.120168697

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