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-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.

Stress Resilience of Spermatozoa and Blood Mononuclear Cells without Prion Protein

“…In conclusion, our observations of PBMCs, spermatozoa and SH-SY5Y cells after induction of different forms of severe cellular stress suggest that PrP C is not directly protective against these stressors in vitro . This, however, does not rule out that PrP C could serve protective functions in vivo , particularly during inflammation, as suggested in several studies in mice (McLennan et al, 2004 ; Martin et al, 2011 ; Gourdain et al, 2012 ; Ezpeleta et al, 2017 ), and goats (Salvesen et al, 2016 , 2017 ).…”

Goats without Prion Protein Display Enhanced Proinflammatory Pulmonary Signaling and Extracellular Matrix Remodeling upon Systemic Lipopolysaccharide Challenge

“…In line with this, the upstream regulator TGF-β showed an increased activation score in PrP C -deficient goats. Indeed, PrP C has been reported to modulate B1 integrin signaling directly ( 34 , 35 ), which is a key regulator of TGF-β-dependent activation of fibroblasts ( 36 ). Homeostasis of the ECM is of major importance for the physiological function of most organs, and is maintained by secretion of proteases and degradation of ECM components, as well as synthesis of collagens ( 37 ).…”

“…Because most PrP C is localized to the cell surface, it has been hypothesized that PrP C binds extracellular proteins and facilitates transmembrane signaling processes ( 44 ). For instance, PrP C desensitized cells to TNF-α by restricting the level of available TNF-receptor present at the plasma membrane of neuroectodermal cells ( 34 ). We have recently proposed that PrP C protects tissues by modulating certain signaling pathways of innate immunity ( 17 ).…”

Retinal Degeneration and Alzheimer’s Disease: An Evolving Link

“…The prion protein (PrP C ) is a ubiquitously expressed protein mainly known for its role as the substrate for PrP-scrapie (PrP Sc ), the principal pathogenic agent responsible for all prion disorders [ 135 , 136 ]. Besides its pathological role, several physiological functions are attributed to PrP C , including protection from oxidative stress, iron uptake, and in regulating the levels of TNFα-cleaving enzyme (TACE) [ 137 , 138 , 139 , 140 , 141 ]. The significance of PrP C in the pathogenesis of AD stems from its role as a receptor for Aβ oligomers [ 142 , 143 ].…”