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Protective role of cellular prion protein against TNF?-mediated inflammation through TACE ?-secretase.

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 TNF? noxious insult. Mechanistically, PrPC coupling to the NADPH oxidase-TACE ?-secretase signaling pathway promotes TACE-mediated cleavage of transmembrane TNF? receptors (TNFRs) and the release of soluble TNFR, which limits the sensitivity of recipient cells to TNF?. We further show that PrPC expression is necessary for TACE ?-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 ?1 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 TNF? insult. Our work provides the prime evidence that in an inflammatory context PrPC adjusts the response of neuronal cells targeted by TNF? through TACE ?-secretase. Our data also support the view that abnormal TACE trafficking and activity in prion diseases originate from a-loss-of-PrPC cytoprotective function.

SUBMITTER: Ezpeleta J

PROVIDER: S-EPMC5550509 | biostudies-literature | 2017 Aug

REPOSITORIES: biostudies-literature

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Protective role of cellular prion protein against TNFα-mediated inflammation through TACE α-secretase.

Ezpeleta Juliette J Boudet-Devaud François F Pietri Mathéa M Baudry Anne A Baudouin Vincent V Alleaume-Butaux Aurélie A Dagoneau Nathalie N Kellermann Odile O Launay Jean-Marie JM Schneider Benoit B

Scientific reports 20170809 1

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 ...[more]

PMID: 28794434

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Dataset Information

Protective role of cellular prion protein against TNF?-mediated inflammation through TACE ?-secretase.

Publications

Protective role of cellular prion protein against TNFα-mediated inflammation through TACE α-secretase.

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