LAUSR

Significance In the fatal brain disorders known as prion diseases, the cellular prion protein (PrPC) is converted into an abnormal structure by other abnormal prion protein molecules. A fragmentation process known as β-cleavage that splits PrPC into two parts is associated with prion diseases, but a clear description of the underlying cleavage mechanism is lacking. Here, we use cultured cells, cell-free systems, and mouse models to show that β-cleavage of PrPC can be performed by two proteins closely related to each other: dipeptidyl peptidase-4 and fibroblast activation protein. By applying inhibitors of these proteins to prion-infected cells, we also show that the β-cleavage activity of dipeptidyl peptidase-4 in particular may be important in the pathogenesis of prion diseases.