Proteasomes and ubiquitin are involved in the turnover of the wild-type prion protein

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Abstract
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 ∼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.