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

Abstract

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. 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. From these results, PrP^c could be considered as a new partner involved in the balance between proliferation and polarization/differentiation in epithelial cells.