Abstract
The cellular prion protein (PrPC) 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 PrPC into its insoluble and aggregation-prone scrapie form (PrPSc) 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 PrPC. To better dissect the role of ubiquitination in PrPC physiology, we focused on the E3 RING ubiquitin ligase tumor necrosis factor receptor (TNFR)-associated factor 6 (TRAF6). Here, we report that PrPC interacts with TRAF6 both in vitro, in cells, and in vivo, in the mouse brain. Transient overexpression of TRAF6 indirectly modulates PrPC ubiquitination and triggers redistribution of PrPC into the insoluble fraction. Importantly, in the presence of wild-type TRAF6, but not a mutant lacking E3 ligase activity, PrPC 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 PrPC redistribution in cells under physiological conditions. This novel interaction may uncover possible mechanisms of cell clearance/reorganization in prion diseases.
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Abbreviations
- PrPC :
-
Cellular prion protein
- PrPSc :
-
Scrapie prion protein
- TRAF6:
-
Tumor necrosis factor receptor-associated factor 6
- DN:
-
Deleted of the N terminus
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Acknowledgements
This work is dedicated to the memory of our beloved friend and colleague Silvia Zucchelli who passed away in 2019 during the writing and reviewing of this manuscript.
The authors wish also to thank Drs Ilaria Poggiolini and Thao Mai Phuong for their involvement in the early stages of the project.
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This work was supported by SISSA intramural funding to GL.
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LM and MC designed and performed the experiments, analyzed the data, and wrote the manuscript; FP and SG analyzed the data and the manuscript; SZ designed the experiments, analyzed the results, and wrote the manuscript; GL designed the experiments, analyzed the results, and wrote the manuscript.
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Silvia Zucchelli was Deceased (April 28, 1972 - October 14, 2019)
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Masperone, L., Codrich, M., Persichetti, F. et al. 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. Mol Neurobiol 59, 1577–1588 (2022). https://doi.org/10.1007/s12035-021-02666-6
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DOI: https://doi.org/10.1007/s12035-021-02666-6