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

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.