NR AVAJ
AU Apodaca,J.; Kim,I.; Rao,H.
TI Cellular tolerance of prion protein PrP in yeast involves proteolysis and the unfolded protein response
QU Biochemical and Biophysical Research Communications 2006 Aug 18; 347(1): 319-26
PT journal article
AB 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.
MH Apoptosis/physiology; Cell Proliferation; Endoplasmic Reticulum/*metabolism; Molecular Chaperones/*metabolism; Prions/*metabolism; Protein Folding; Recombinant Proteins/metabolism; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't; Saccharomyces cerevisiae/*physiology; Saccharomyces cerevisiae Proteins/*metabolism; Ubiquitin/*metabolism
AD Institute of Biotechnology, Department of Molecular Medicine, The University of Texas Health Science Center, San Antonio, 78245, USA
SP englisch
PO USA