title: Efficient inhibition of infectious prions multiplication and release by targeting the exosomal pathway.
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.
authors.affiliation: UMR INRA/ENVT 1225, Interactions Hôte Agent Pathogène, Toulouse, France. d.vilette@envt.fr.
authors.forename: Didier
authors.initials: D
authors.lastname: Vilette
authors.affiliation: CNRS, UMR5239, Laboratoire de Biologie Moléculaire de la Cellule (LBMC), ENS Lyon, 46 allée d'Italie, 69364, Lyon 7, France.|Inserm, U836, Neurodégénérescence et Plasticité, Institute of Neuroscience, Grenoble, France.
authors.forename: Karine
authors.initials: K
authors.lastname: Laulagnier
authors.affiliation: UMR INRA/ENVT 1225, Interactions Hôte Agent Pathogène, Toulouse, France.
authors.forename: Alvina
authors.initials: A
authors.lastname: Huor
authors.affiliation: Centre International de Recherche en Infectiologie (CIRI), INSERM U1111, CNRS UMR5308, UCBL, ENS Lyon, Lyon, France.
authors.forename: Sandrine
authors.initials: S
authors.lastname: Alais
authors.affiliation: Institut Curie, CNRS-UMR144-Structure and Membrane Compartments, 26 rue d'Ulm, 75248, Paris Cedex 05, France.
authors.forename: Sabrina
authors.initials: S
authors.lastname: Simoes
authors.affiliation: Institut Curie, CNRS-UMR144-Structure and Membrane Compartments, 26 rue d'Ulm, 75248, Paris Cedex 05, France.
authors.forename: Romao
authors.initials: R
authors.lastname: Maryse
authors.affiliation: Institut de Médecine Régénératrice et de Biothérapie (I.M.R.B.), Physiopathologie, diagnostic et thérapie cellulaire des affections neurodégénératives, INSERM Université Montpellier 1 U1040 CHU de Montpellier, Université Montpellier 1, Montpellier, France.
authors.forename: Monique
authors.initials: M
authors.lastname: Provansal
authors.affiliation: Institut de Médecine Régénératrice et de Biothérapie (I.M.R.B.), Physiopathologie, diagnostic et thérapie cellulaire des affections neurodégénératives, INSERM Université Montpellier 1 U1040 CHU de Montpellier, Université Montpellier 1, Montpellier, France.
authors.forename: Sylvain
authors.initials: S
authors.lastname: Lehmann
authors.affiliation: UMR INRA/ENVT 1225, Interactions Hôte Agent Pathogène, Toulouse, France.
authors.forename: Olivier
authors.initials: O
authors.lastname: Andreoletti
authors.affiliation: CNRS, UMR5239, Laboratoire de Biologie Moléculaire de la Cellule (LBMC), ENS Lyon, 46 allée d'Italie, 69364, Lyon 7, France.
authors.forename: Laurent
authors.initials: L
authors.lastname: Schaeffer
authors.affiliation: Institut Curie, CNRS-UMR144-Structure and Membrane Compartments, 26 rue d'Ulm, 75248, Paris Cedex 05, France.
authors.forename: Graça
authors.initials: G
authors.lastname: Raposo
authors.affiliation: CNRS, UMR5239, Laboratoire de Biologie Moléculaire de la Cellule (LBMC), ENS Lyon, 46 allée d'Italie, 69364, Lyon 7, France. Pascal.Leblanc@ens-lyon.fr.
authors.forename: Pascal
authors.initials: P
authors.lastname: Leblanc
mesh_terms: D000814:Aniline Compounds / Q000494:pharmacology; D000818:Animals; D001597:Benzylidene Compounds / Q000494:pharmacology; D002460:Cell Line; D045744:Cell Line, Tumor; D002518:Ceramides / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000235:genetics; D056827:Endosomal Sorting Complexes Required for Transport / Q000235:genetics*; D055354:Exosomes / Q000235:genetics* / Q000378:metabolism / Q000648:ultrastructure; D006801:Humans; D015151:Immunoblotting; D008822:Mice, Transgenic; D018613:Microscopy, Confocal; D008854:Microscopy, Electron; D011328:Prions / Q000235:genetics* / Q000378:metabolism; D021381:Protein Transport / Q000187:drug effects / Q000235:genetics; D034622:RNA Interference; D011817:Rabbits; D012756:Sheep; D015398:Signal Transduction / Q000235:genetics*; D014157:Transcription Factors / Q000235:genetics; D000099177:Tsg101 Protein
chemical_list: D000814:Aniline Compounds; D001597:Benzylidene Compounds; D002518:Ceramides; D004268:DNA-Binding Proteins; D056827:Endosomal Sorting Complexes Required for Transport; D011328:Prions; D014157:Transcription Factors; D000099177:Tsg101 Protein; C468773:GW 4869
keywords: Ceramide; Cholesterol; ESCRT; Exosomes; PrPSc; PrPres; Prions