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

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Autores principales:	Juliette Ezpeleta, François Boudet-Devaud, Mathéa Pietri, Anne Baudry, Vincent Baudouin, Aurélie Alleaume-Butaux, Nathalie Dagoneau, Odile Kellermann, Jean-Marie Launay, Benoit Schneider
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2017
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/98b23f663c354ca58b1295e144d129b8
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spelling	oai:doaj.org-article:98b23f663c354ca58b1295e144d129b82021-12-02T16:06:43ZProtective role of cellular prion protein against TNFα-mediated inflammation through TACE α-secretase10.1038/s41598-017-08110-x2045-2322https://doaj.org/article/98b23f663c354ca58b1295e144d129b82017-08-01T00:00:00Zhttps://doi.org/10.1038/s41598-017-08110-xhttps://doaj.org/toc/2045-2322Abstract 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.Juliette EzpeletaFrançois Boudet-DevaudMathéa PietriAnne BaudryVincent BaudouinAurélie Alleaume-ButauxNathalie DagoneauOdile KellermannJean-Marie LaunayBenoit SchneiderNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 7, Iss 1, Pp 1-13 (2017)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Juliette Ezpeleta François Boudet-Devaud Mathéa Pietri Anne Baudry Vincent Baudouin Aurélie Alleaume-Butaux Nathalie Dagoneau Odile Kellermann Jean-Marie Launay Benoit Schneider Protective role of cellular prion protein against TNFα-mediated inflammation through TACE α-secretase
description	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.
format	article
author	Juliette Ezpeleta François Boudet-Devaud Mathéa Pietri Anne Baudry Vincent Baudouin Aurélie Alleaume-Butaux Nathalie Dagoneau Odile Kellermann Jean-Marie Launay Benoit Schneider
author_facet	Juliette Ezpeleta François Boudet-Devaud Mathéa Pietri Anne Baudry Vincent Baudouin Aurélie Alleaume-Butaux Nathalie Dagoneau Odile Kellermann Jean-Marie Launay Benoit Schneider
author_sort	Juliette Ezpeleta
title	Protective role of cellular prion protein against TNFα-mediated inflammation through TACE α-secretase
title_short	Protective role of cellular prion protein against TNFα-mediated inflammation through TACE α-secretase
title_full	Protective role of cellular prion protein against TNFα-mediated inflammation through TACE α-secretase
title_fullStr	Protective role of cellular prion protein against TNFα-mediated inflammation through TACE α-secretase
title_full_unstemmed	Protective role of cellular prion protein against TNFα-mediated inflammation through TACE α-secretase
title_sort	protective role of cellular prion protein against tnfα-mediated inflammation through tace α-secretase
publisher	Nature Portfolio
publishDate	2017
url	https://doaj.org/article/98b23f663c354ca58b1295e144d129b8
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Protective role of cellular prion protein against TNFα-mediated inflammation through TACE α-secretase

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