NR AMVT
AU Yedidia,Y.; Horonchik,L.; Tzaban,S.; Yanai,A.; Taraboulos,A.
TI Proteasomes and ubiquitin are involved in the turnover of the wild-type prion protein
QU EMBO Journal 2001 Oct 1; 20(19): 5383-91
PT journal article
AB Prion diseases propagate by converting a normal glycoprotein of the host, PrPc, into a pathogenic "prion" conformation. Several misfolding mutants of PrPc are degraded through the ER-associated degradation (ERAD)-proteasome pathway. In their infectious form, prion diseases such as bovine spongiform encephalopathy involve PrPc of wild-type sequence. In contrast to mutant PrP, wild-type PrPc was hitherto thought to be stable in the ER and thus immune to ERAD. Using proteasome inhibitors, we now show that approximately 10% of nascent PrPc molecules are diverted into the ERAD pathway. Cells incubated with N-acetyl-leucinal-leucinal-norleucinal (ALLN), lactacystin or MG132 accumulated both detergent-soluble and insoluble PrP species. The insoluble fraction included an unglycosylated 26 kDa PrP species with a protease-resistant core, and a M(r) "ladder" that contained ubiquitylated PrP. Our results show for the first time that wild-type PrPc molecules are subjected to ERAD, in the course of which they are dislocated into the cytosol and ubiquitylated. The presence of wild-type PrP molecules in the cytosol may have potential pathogenic implications.
MH Animal; Brefeldin A/pharmacology; CHO Cells; Cysteine Endopeptidases/*metabolism; Cytoplasm/metabolism; Endoplasmic Reticulum/metabolism; Hamsters; Leupeptins/pharmacology; Membrane Proteins/metabolism; Mice; Multienzyme Complexes/antagonists & inhibitors/*metabolism; PrPc Proteins/*metabolism; Protease Inhibitors/pharmacology; Protein Processing, Post-Translational; Solubility; Support, Non-U.S. Gov't; Tumor Cells, Cultured; Ubiquitin/*metabolism
AD Department of Molecular Biology, The Hebrew University-Hadassah Medical School, PO Box 12272, Jerusalem 91120, Israel.
SP englisch
PO England