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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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Project description:Metabolic dysfunction-associated steatohepatitis-driven hepatocellular carcinoma (MASH-HCC) is a global clinical challenge for which there is a limited understanding of disease pathogenesis and a subsequent lack of therapeutic interventions. We previously identified that tumor necrosis factor-alpha (TNF-α) upregulated apoptosis antagonizing transcription factor (AATF) in MASH. Here, we investigated the effect of TNF-α converting enzyme (TACE) inhibition as a promising targeted therapy against AATF-mediated steatohepatitis to hepatocarcinogenesis. A preclinical murine model that recapitulates human MASH-HCC was used in the study. C57Bl/6 mice were fed with chow diet normal water (CD) or western diet sugar water (WD) along with a low dose of carbon tetrachloride (CCl4; 0.2 μL·g-1, weekly) for 24 weeks. TACE activity, TNF-α levels, and AATF expression were measured. The mice were treated with the TACE inhibitor Marimastat for 12 weeks, followed by analyses of liver injury, fibrosis, inflammation, and oncogenic signaling. In vitro experiments using stable clones of AATF control and AATF knockdown were also conducted. We found that AATF expression was upregulated in WD/CCl4 mice, which developed severe MASH at 12 weeks and advanced fibrosis with HCC at 24 weeks. WD/CCl4 mice showed increased TACE activity with reduced hepatic expression of sirtuin 1 (Sirt1) and tissue inhibitor of metalloproteinase 3 (Timp3). The involvement of the SIRT1/TIMP3/TACE axis was confirmed by the release of TNF-α, which upregulated AATF, a key molecular driver of MASH-HCC. Interestingly, TACE inhibition by Marimastat reduced liver injury, dyslipidemia, AATF expression, and oncogenic signaling, effectively preventing hepatocarcinogenesis. Furthermore, Marimastat inhibited the activation of JNK, ERK1/2, and AKT, which are key regulators of tumorigenesis in WD/CCl4 mice and in AATF control cells, but had no effect on AATF knockdown cells. This study shows that TACE inhibition prevents AATF-mediated inflammation, fibrosis, and oncogenesis in MASH-HCC, offering a potential target for therapeutic intervention.

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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