Copper and zinc cause delivery of the prion protein from the plasma membrane to a subset of early endosomes and the Golgi

The cellular isoform of prion protein (PrPC) is a plasma membrane glycoprotein whose conformational conversion into PrPSc is the central molecular event in the propagation of infectious prions. However, the physiological function of PrPC has remained uncertain. The finding that PrPC binds copper ions with low micromolar affinity, coupled with several other observations, has led to the proposal that the protein plays a role in copper homeostasis. Using biochemical techniques, we had shown previously that copper ions rapidly and reversibly stimulate endocytosis of PrPC from the cell surface. In this report, we employ immunofluorescence microscopy to further investigate the specificity and kinetics of metal effects on PrPC trafficking and to identify the intracellular compartments to which internalized PrPC is delivered in response to copper and zinc. We find that both of these metals stimulate redistribution of surface PrPC to a subset of transferrin-containing early endosomes as well as to Golgi compartments. These results are consistent with models in which PrPC plays a role in the cellular uptake or efflux of transition metals.