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Although cellular prion protein PrP C  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 PrP C  displays the intrinsic capacity to protect neuronal cells from a pro-inflammatory TNFα noxious insult. Mechanistically, PrP C  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 PrP C  expression is necessary for TACE α-secretase to stay at the plasma membrane in an active state for TNFR shedding. Such PrP C  control of TACE localization depends on PrP C  modulation of β1 integrin signaling and downstream activation of ROCK-I and PDK1 kinases. Loss of PrP C  provokes TACE internalization, which in turn cancels TACE-mediated cleavage of TNFR and renders PrP C -depleted neuronal cells as well as PrP C  knockout mice highly vulnerable to pro-inflammatory TNFα insult. Our work provides the prime evidence that in an inflammatory context PrP C  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-PrP C  cytoprotective function.

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