The Cellular Prion Protein PrPc Is Involved in the Proliferation of Epithelial Cells and in the Distribution of Junction-Associated Proteins

Background The physiological function of the ubiquitous cellular prion protein, PrP c , is still under debate. It was essentially studied in nervous system, but poorly investigated in epithelial cells. We previously reported that PrP c is targeted to cell–cell junctions of polarized epithelial cells, where it interacts with c-Src. Methodology/Findings We show here that, in cultured human enterocytes and in intestine in vivo , the mature PrP c is differentially targeted either to the nucleus in dividing cells or to cell–cell contacts in polarized/differentiated cells. By proteomic analysis, we demonstrate that the junctional PrP c interacts with cytoskeleton-associated proteins, such as gamma- and beta-actin, alpha-spectrin, annexin A2, and with the desmosome-associated proteins desmoglein, plakoglobin and desmoplakin. In addition, co-immunoprecipitation experiments revealed complexes associating PrP c , desmoglein and c-Src in raft domains. Through siRNA strategy, we show that PrP c is necessary to complete the process of epithelial cell proliferation and for the sub-cellular distribution of proteins involved in cell architecture and junctions. Moreover, analysis of the architecture of the intestinal epithelium of PrP c knock-out mice revealed a net decrease in the size of desmosomal junctions and, without change in the amount of BrdU incorporation, a shortening of the length of intestinal villi. Conclusions/Significance From these results, PrP c could be considered as a new partner involved in the balance between proliferation and polarization/differentiation in epithelial cells.