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The cellular prion protein PrPc is a partner of the Wnt pathway in intestinal epithelial cells

15 sept. 2015Molecular Biology of the Cell

DOI : 10.1091/mbc.e14-11-1534

Auteurs

Laura S. Besnier, Philippe Cardot, Barbara Da Rocha, Anthony Simon, Damarys Loew, Christophe Klein, Béatrice Riveau, Michel Lacasa, Caroline Clair, Monique Rousset, Sophie Thenet

Résumé

We reported previously that the cellular prion protein (PrPc) is a component of desmosomes and contributes to the intestinal barrier function. We demonstrated also the presence of PrPcin the nucleus of proliferating intestinal epithelial cells. Here we sought to decipher the function of this nuclear pool. In human intestinal cancer cells Caco-2/TC7 and SW480 and normal crypt-like HIEC-6 cells, PrPcinteracts, in cytoplasm and nucleus, with γ-catenin, one of its desmosomal partners, and with β-catenin and TCF7L2, effectors of the canonical Wnt pathway. PrPcup-regulates the transcriptional activity of the β-catenin/TCF7L2 complex, whereas γ-catenin down-regulates it. Silencing of PrPcresults in the modulation of several Wnt target gene expressions in human cells, with different effects depending on their Wnt signaling status, and in mouse intestinal crypt cells in vivo. PrPcalso interacts with the Hippo pathway effector YAP, suggesting that it may contribute to the regulation of gene transcription beyond the β-catenin/TCF7L2 complex. Finally, we demonstrate that PrPcis required for proper formation of intestinal organoids, indicating that it contributes to proliferation and survival of intestinal progenitors. In conclusion, PrPcmust be considered as a new modulator of the Wnt signaling pathway in proliferating intestinal epithelial cells.