Cellular tolerance of prion protein PrP in yeast involves proteolysis and the unfolded protein response

Jennifer Apodaca, Ikjin Kim, Hai Rao

Research output: Contribution to journalArticlepeer-review

38 Scopus citations


Secretory proteins undergo a stringent quality control process in the endoplasmic reticulum (ER). Misfolded ER proteins are returned to the cytosol and destroyed by the proteasome. Prion protein PrP is degraded by the proteasome in mammalian cells. However, the significance of proteolysis on PrP-induced cell death is controversial. Moreover, the specific pathway involved in PrP degradation remains unknown. Here, we demonstrate that the unglycosylated form of human PrP is subjected to the ER-associated protein degradation (ERAD) process in the yeast Saccharomyces cerevisiae. We also show that unglycosylated PrP is degraded by the Hrd1-Hrd3 pathway. Accumulation of misfolded proteins triggers the unfolded protein response (UPR), which promotes substrate refolding. Interestingly, we find that the expression of PrP leads to growth impairment in cells deficient in UPR and ERAD. These findings raise the possibility that decreased UPR activity and proteolysis may contribute to the pathogenesis of some prion-related diseases.

Original languageEnglish (US)
Pages (from-to)319-326
Number of pages8
JournalBiochemical and Biophysical Research Communications
Issue number1
StatePublished - Aug 18 2006


  • ERAD
  • PrP
  • Proteasome
  • UPR
  • Ubiquitin

ASJC Scopus subject areas

  • Biophysics
  • Biochemistry
  • Molecular Biology
  • Cell Biology


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