Figure 2.

PrP^C–ROCK connection controls TACE trafficking and cell sensitivity to TNFα. By toning down the integrin-dependent RhoA activation, PrP^C lowers the enzymatic activity of the ROCK/PDK1 complex that permits the α-secretase TACE to stay at the plasma membrane. TACE cleaves cell surface TNFR1 and releases sTNFR1 that neutralizes sTNFα and thereby limits the cell sensitivity to sTNFα (left). In PrP^C-depleted neurons, the overactivation of ROCK/PDK1 module provoked by the micro-clustering of β1 integrins triggers TACE internalization and neutralization in caveolin-1 enriched vesicles. Internalized TACE is uncoupled from TNFR1 substrate that accumulates at the cell surface and renders PrP^C-depleted neurons hypervulnerable to sTNFα toxicity (middle). In PrP^C-depleted neurons, pharmacological inhibition of ROCK decreases PDK1 activity, which permits TACE to locate back to the plasma membrane and to restore TACE shedding activity toward TNFR1 (right).