A protein required for prion generation: [URE3] induction requires the Ras-regulated Mks1 protein.
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 mks1Delta strains, de novo generation of the [URE3] prion is blocked, although [URE3] introduced from another strain is expressed and propagates stably. Ras2(Val19) 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.
Edskes
H K
HK
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, USA.
Wickner
R B
RB
D000242:Cyclic AMP / Q000502:physiology; D005656:Fungal Proteins / Q000502:physiology*; D011328:Prions / Q000096:biosynthesis*; D012097:Repressor Proteins; D012441:Saccharomyces cerevisiae / Q000502:physiology*; D029701:Saccharomyces cerevisiae Proteins; D014157:Transcription Factors; D018631:ras Proteins / Q000502:physiology*
D005656:Fungal Proteins; C080921:MKS1 protein, S cerevisiae; D011328:Prions; D012097:Repressor Proteins; D029701:Saccharomyces cerevisiae Proteins; D014157:Transcription Factors; D000242:Cyclic AMP; D018631:ras Proteins