Protection from cytosolic prion protein toxicity by modulation of protein translocation

• Published in: The EMBO journal 2004-11, Vol.23 (23), p.4550-4559
• Main Authors: Rane, Neena S, Yonkovich, Jesse L, Hegde, Ramanujan S
• Format: Article
• Language: English
• Subjects: Animals; Cell Death - physiology; Cells, Cultured; Cytosol - metabolism; cytotoxicity; EMBO20; EMBO24; Endoplasmic Reticulum - metabolism; prion protein; proteasomal degradation; Proteasome Endopeptidase Complex - metabolism; protein aggregation; Protein Binding; Protein Folding; Protein Sorting Signals; protein translocation; Protein Transport; Proteins; PrPC Proteins - biosynthesis; PrPC Proteins - metabolism; Translocation
• ISSN: 0261-4189; 1460-2075
• DOI: 10.1038/sj.emboj.7600462

Failure to promptly dispose of undesirable proteins is associated with numerous diseases. In the case of cellular prion protein (PrP), inhibition of the proteasome pathway can generate a highly aggregation‐prone, cytotoxic form of PrP implicated in neurodegeneration. However, the predominant mechanisms that result in delivery of PrP, ordinarily targeted to the secretory pathway, to cytosolic proteasomes have been unclear. By accurately measuring the in vivo fidelity of protein translocation into the endoplasmic reticulum (ER), we reveal a slight inefficiency in PrP signal sequence function that generates proteasomally degraded cytosolic PrP. Attenuating this source of cytosolic PrP completely eliminates the dependence on proteasomes for PrP degradation. This allows cells to tolerate both higher expression levels and decreased proteasomal capacity without succumbing to the adverse consequences of misfolded PrP. Thus, the generation of potentially toxic cytosolic PrP is controlled primarily during its initial translocation into the ER. These results suggest that a substantial proportion of the cell's constitutive proteasomal burden may consist of proteins that, like PrP, fail to cotranslationally enter the secretory pathway with high fidelity.