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Proteasomes and ubiquitin are involved in the turnover of the wild‐type prion protein
Author(s) -
Yedidia Yifat,
Horonchik Lior,
Tzaban Salit,
Yanai Anat,
Taraboulos Albert
Publication year - 2001
Publication title -
the embo journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 7.484
H-Index - 392
eISSN - 1460-2075
pISSN - 0261-4189
DOI - 10.1093/emboj/20.19.5383
Subject(s) - biology , proteasome , ubiquitin , protein turnover , ubiquitins , prion protein , ubiquitin protein ligases , genetics , biochemistry , microbiology and biotechnology , ubiquitin ligase , protein biosynthesis , gene , disease , medicine , pathology
Prion diseases propagate by converting a normal glycoprotein of the host, PrP C , into a pathogenic ‘prion’ conformation. Several misfolding mutants of PrP C are degraded through the ER‐associated degradation (ERAD)–proteasome pathway. In their infectious form, prion diseases such as bovine spongiform encephalopathy involve PrP C of wild‐type sequence. In contrast to mutant PrP, wild‐type PrP C was hitherto thought to be stable in the ER and thus immune to ERAD. Using proteasome inhibitors, we now show that ∼10% of nascent PrP C 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 PrP C 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.