1. Protective role of cellular prion protein against TNFα-mediated inflammation through TACE α-secretase
- Author
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François Boudet-Devaud, Vincent Baudouin, Aurélie Alleaume-Butaux, Anne Baudry, Mathéa Pietri, Odile Kellermann, Benoit Schneider, Jean-Marie Launay, Juliette Ezpeleta, Nathalie Dagoneau, Toxicité environnementale, cibles thérapeutiques, signalisation cellulaire (T3S - UMR_S 1124), Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP)-Institut National de la Santé et de la Recherche Médicale (INSERM), Marqueurs cardiovasculaires en situation de stress (MASCOT (UMR_S_942 / U942)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP)-Université Sorbonne Paris Nord, SCHNEIDER, Benoit, Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité)-Université Sorbonne Paris Nord
- Subjects
0301 basic medicine ,Science ,animal diseases ,media_common.quotation_subject ,Inflammation ,ADAM17 Protein ,Protein Serine-Threonine Kinases ,Prion Proteins ,Article ,Cell Line ,Mice ,03 medical and health sciences ,mental disorders ,medicine ,Animals ,PrPC Proteins ,[SDV.NEU] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC] ,[SDV.BBM.BC]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biochemistry [q-bio.BM] ,Internalization ,Receptor ,[SDV.BBM.BC] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biochemistry [q-bio.BM] ,media_common ,Neurons ,rho-Associated Kinases ,Multidisciplinary ,Tumor Necrosis Factor-alpha ,Chemistry ,Kinase ,NADPH Oxidases ,Pyruvate Dehydrogenase Acetyl-Transferring Kinase ,Transmembrane protein ,nervous system diseases ,Cell biology ,030104 developmental biology ,Receptors, Tumor Necrosis Factor, Type I ,Knockout mouse ,Medicine ,[SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC] ,Tumor necrosis factor alpha ,Amyloid Precursor Protein Secretases ,Inflammation Mediators ,Signal transduction ,medicine.symptom ,Signal Transduction - Abstract
Although cellular prion protein PrPC is well known for its implication in Transmissible Spongiform Encephalopathies, its functions remain elusive. Combining in vitro and in vivo approaches, we here show that PrPC displays the intrinsic capacity to protect neuronal cells from a pro-inflammatory TNFα noxious insult. Mechanistically, PrPC coupling to the NADPH oxidase-TACE α-secretase signaling pathway promotes TACE-mediated cleavage of transmembrane TNFα receptors (TNFRs) and the release of soluble TNFR, which limits the sensitivity of recipient cells to TNFα. We further show that PrPC expression is necessary for TACE α-secretase to stay at the plasma membrane in an active state for TNFR shedding. Such PrPC control of TACE localization depends on PrPC modulation of β1 integrin signaling and downstream activation of ROCK-I and PDK1 kinases. Loss of PrPC provokes TACE internalization, which in turn cancels TACE-mediated cleavage of TNFR and renders PrPC-depleted neuronal cells as well as PrPC knockout mice highly vulnerable to pro-inflammatory TNFα insult. Our work provides the prime evidence that in an inflammatory context PrPC adjusts the response of neuronal cells targeted by TNFα through TACE α-secretase. Our data also support the view that abnormal TACE trafficking and activity in prion diseases originate from a-loss-of-PrPC cytoprotective function.
- Published
- 2017