Abstract
Despite its multi-faceted role in neurodegenerative diseases, the physiological function of the prion protein (PrP) has remained elusive. On the basis of its evolutionary relationship to ZIP metal ion transporters, we considered that PrP may contribute to the morphogenetic reprogramming of cells underlying epithelial-to-mesenchymal transitions (EMT). Consistent with this hypothesis, PrP transcription increased more than tenfold during EMT, and stable PrP-deficient cells failed to complete EMT in a mammalian cell model. A global comparative proteomics analysis identified the neural cell adhesion molecule 1 (NCAM1) as a candidate mediator of this impairment, which led to the observation that PrP-deficient cells fail to undergo NCAM1 polysialylation during EMT. Surprisingly, this defect was caused by a perturbed transcription of the polysialyltransferase ST8SIA2 gene. Proteomics data pointed toward β-catenin as a transcriptional regulator affected in PrP-deficient cells. Indeed, pharmacological blockade or siRNA-based knockdown of β-catenin mimicked PrP-deficiency in regards to NCAM1 polysialylation. Our data established the existence of a PrP-ST8SIA2-NCAM signaling loop, merged two mature fields of investigation and offer a simple model for explaining phenotypes linked to PrP.
Highlights
Ever since evidence mounted that the prion protein is the causative agent underlying prion diseases [1], yet is widely expressed in healthy vertebrate cells of diverse lineages, scientists have sought to uncover the physiological role of this protein [2]
To address if transcriptional activation of prion protein (PrP) is essential for epithelial-to-mesenchymal transitions (EMT) or represents merely a correlative phenomenon, we compared the execution of this program in NMuMG wildtype cells or derivative clones whose levels of PrP expression were diminished by CRISPR/ Cas9 knockout technology or stable knockdown of PrP transcripts (Fig 1d) [29]
When these alternative PrP-deficiency models were monitored before and after exposure to transforming growth factor beta 1 (TGFB1), several observations were made: (i) PrP-deficient NMuMG cells exhibited defects in cell-cell contacts even prior to EMT-induction that manifested in a perturbed distribution of E-cadherin at the plasma membrane, characterized by a zigzag, non-continuous appearance of its signals along the plasma membrane. (ii) Upon addition of TGFB1, PrP-deficient cells acquired a less pronounced fibroblastoid phenotype than wt cells
Summary
Ever since evidence mounted that the prion protein is the causative agent underlying prion diseases [1], yet is widely expressed in healthy vertebrate cells of diverse lineages, scientists have sought to uncover the physiological role of this protein [2]. The cellular prion protein (PrPC) has been tied to diverse cellular activities ranging from cell adhesion to ion transport, neuritogenesis, modulation of electrophysiological currents and circadian regulation (reviewed in [3,4,5,6]) but the molecular mechanism of its proposed involvement in these and other activities has remained largely enigmatic. It is a challenge to identify a prevailing theme in this body of literature, a reality reflected in the widely held view that the role of this protein is complex, PLOS ONE | DOI:10.1371/journal.pone.0133741. It is a challenge to identify a prevailing theme in this body of literature, a reality reflected in the widely held view that the role of this protein is complex, PLOS ONE | DOI:10.1371/journal.pone.0133741 August 19, 2015
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