The E3 Ubiquitin Ligase TRAF6 Interacts with the Cellular Prion Protein and Modulates Its Solubility and Recruitment to Cytoplasmic p62/SQSTM1-Positive Aggresome-Like Structures

• Published in: Molecular neurobiology Vol. 59; no. 3; pp. 1577 - 1588
• Main Authors: Masperone, Lara, Codrich, Marta, Persichetti, Francesca, Gustincich, Stefano, Zucchelli, Silvia, Legname, Giuseppe
• Format: Journal Article
• Language: English
• Published: New York Springer US 01.03.2022; Springer Nature B.V
• Subjects: Alzheimer's disease; Animals; Axonogenesis; Biomedical and Life Sciences; Biomedicine; Brain; Cell adhesion; Cell Biology; Cell signaling; Glutamic acid receptors (ionotropic); Homeostasis; Inclusion bodies; Mice; N-Methyl-D-aspartic acid receptors; Neurobiology; Neurodegenerative diseases; Neurology; Neurosciences; Parkinson's disease; Physiology; Prion protein; Prion Proteins - metabolism; Proteasomes; Protein Binding; Proteins; Quality control; Scrapie; Sequestosome-1 Protein - metabolism; Signal transduction; Solubility; TNF Receptor-Associated Factor 6 - metabolism; TRAF6 protein; Tumor necrosis factor receptors; Tumor necrosis factor-TNF; Ubiquitin; Ubiquitin-protein ligase; Ubiquitin-Protein Ligases - metabolism; Ubiquitination; Ubiquitination; Aggresomes; Cellular prion protein; TRAF6
• ISSN: 0893-7648; 1559-1182
• DOI: 10.1007/s12035-021-02666-6

The cellular prion protein (PrP C ) is a ubiquitous glycoprotein highly expressed in the brain where it is involved in neurite outgrowth, copper homeostasis, NMDA receptor regulation, cell adhesion, and cell signaling. Conformational conversion of PrP C into its insoluble and aggregation-prone scrapie form (PrP Sc ) is the trigger for several rare devastating neurodegenerative disorders, collectively referred to as prion diseases. Recent work indicates that the ubiquitin–proteasome system is involved in quality control of PrP C . To better dissect the role of ubiquitination in PrP C physiology, we focused on the E3 RING ubiquitin ligase tumor necrosis factor receptor (TNFR)-associated factor 6 (TRAF6). Here, we report that PrP C interacts with TRAF6 both in vitro, in cells, and in vivo, in the mouse brain. Transient overexpression of TRAF6 indirectly modulates PrP C ubiquitination and triggers redistribution of PrP C into the insoluble fraction. Importantly, in the presence of wild-type TRAF6, but not a mutant lacking E3 ligase activity, PrP C accumulates into cytoplasmic aggresome-like inclusions containing TRAF6 and p62/SQSTM1. Our results suggest that TRAF6 ligase activity could exert a role in the regulation of PrP C redistribution in cells under physiological conditions. This novel interaction may uncover possible mechanisms of cell clearance/reorganization in prion diseases.