1. Efficient inhibition of infectious prions multiplication and release by targeting the exosomal pathway.
- Author
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Vilette D, Laulagnier K, Huor A, Alais S, Simoes S, Maryse R, Provansal M, Lehmann S, Andreoletti O, Schaeffer L, Raposo G, and Leblanc P
- Subjects
- Aniline Compounds pharmacology, Animals, Benzylidene Compounds pharmacology, Cell Line, Cell Line, Tumor, Ceramides metabolism, DNA-Binding Proteins genetics, Exosomes metabolism, Exosomes ultrastructure, Humans, Immunoblotting, Mice, Transgenic, Microscopy, Confocal, Microscopy, Electron, Prions metabolism, Protein Transport drug effects, Protein Transport genetics, RNA Interference, Rabbits, Sheep, Transcription Factors genetics, Endosomal Sorting Complexes Required for Transport genetics, Exosomes genetics, Prions genetics, Signal Transduction genetics
- Abstract
Exosomes are secreted membrane vesicles of endosomal origin present in biological fluids. Exosomes may serve as shuttles for amyloidogenic proteins, notably infectious prions, and may participate in their spreading in vivo. To explore the significance of the exosome pathway on prion infectivity and release, we investigated the role of the endosomal sorting complex required for transport (ESCRT) machinery and the need for ceramide, both involved in exosome biogenesis. Silencing of HRS-ESCRT-0 subunit drastically impairs the formation of cellular infectious prion due to an altered trafficking of cholesterol. Depletion of Tsg101-ESCRT-I subunit or impairment of the production of ceramide significantly strongly decreases infectious prion release. Together, our data reveal that ESCRT-dependent and -independent pathways can concomitantly regulate the exosomal secretion of infectious prion, showing that both pathways operate for the exosomal trafficking of a particular cargo. These data open up a new avenue to regulate prion release and propagation.
- Published
- 2015
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