Recruitment of cellular prion protein to mitochondrial raft-like microdomains contributes to apoptosis execution

Abstract

PrP ^C is identified as a new component of mitochondrial raft-like microdomains in T cells undergoing CD95/Fas–mediated apoptosis, and microtubular network integrity and function could play a role in the redistribution of PrP ^C from the plasma membrane to the mitochondria.

Abstract

We examined the possibility that cellular prion protein (PrP ^C) plays a role in the receptor-mediated apoptotic pathway. We first found that CD95/Fas triggering induced a redistribution of PrP ^C to the mitochondria of T lymphoblastoid CEM cells via a mechanism that brings into play microtubular network integrity and function. In particular, we demonstrated that PrP ^C was redistributed to raft-like microdomains at the mitochondrial membrane, as well as at endoplasmic reticulum-mitochondria–associated membranes. Our in vitro experiments also demonstrated that, although PrP ^C had such an effect on mitochondria, it induced the loss of mitochondrial membrane potential and cytochrome c release only after a contained rise of calcium concentration. Finally, the involvement of PrP ^C in apoptosis execution was also analyzed in PrP ^C-small interfering RNA–transfected cells, which were found to be significantly less susceptible to CD95/Fas–induced apoptosis. Taken together, these results suggest that PrP ^C might play a role in the complex multimolecular signaling associated with CD95/Fas receptor–mediated apoptosis.