The destabilization of lipid membranes induced by the C-terminal fragment of caspase 8-cleaved bid is inhibited by the N-terminal fragment

Bid is a proapoptotic, BH8-domain-only member of the Bcl-2 family. In Fas-i nduced apoptosis, Bid is activated through cleavage by caspase 8 into a 15, 5-kDa C-terminal fragment (t(c)Bid) and a 6.5 kDa N-terminal fragment (t(n) Bid). Following the cleavage, t(c)Bid translocates to the mitochondria and promotes the release of cytochrome c into the cytosol by a mechanism that i s not understood. Here we report that recombinant t(c)Bid can act as a memb rane destabilizing agent, t(c)Bid induces destabilization and breaking of p lanar lipid bilayers without appearance of ionic channels; its destabilizin g activity is comparable with that of Bax and at least 30-fold higher than that of full-length Bid. Consistently, t(c)Bid, but not full-length Bid, pe rmeabilizes liposomes at physiological pH. The destabilizing effect of t(c) Bid on liposomes and planar bilayers is independent of the BH3 domain. In c ontrast, mutations in the BH3 domain impair t(c)Bid ability to induce cytoc hrome c release from mitochondria. The permeabilizing effect of t(c)Bid on planar bilayers, liposomes, and mitochondria can be inhibited by t(c)Bid. I n conclusion, our results suggest a dual role for Bid: BH3-independent memb rane destabilization and BH3-dependent interaction with other proteins. Mor eover, the dissociation of Bid after cleavage by caspase 8 represents an ad ditional step at which apoptosis may be regulated.