The Destabilization of Lipid Membranes Induced by the C-terminal Fragment of Caspase 8-cleaved Bid Is Inhibited by the N-terminal Fragment

• Published in: The Journal of biological chemistry Vol. 275; no. 30; pp. 22713 - 22718
• Main Authors: Kudla, Grzegorz, Montessuit, Sylvie, Eskes, Robert, Berrier, Catherine, Martinou, Jean-Claude, Ghazi, Alexandre, Antonsson, Bruno
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 28.07.2000; American Society for Biochemistry and Molecular Biology
• Subjects: Animals; BH3 Interacting Domain Death Agonist Protein; Carrier Proteins - genetics; Carrier Proteins - metabolism; Caspase 8; Caspase 9; Caspases - metabolism; Hydrolysis; Lipid Bilayers; Liposomes; Mice; Mitochondria - metabolism; Mutation; Proto-Oncogene Proteins c-bcl-2 - chemistry; Proto-Oncogene Proteins c-bcl-2 - metabolism; Recombinant Proteins - chemistry; Recombinant Proteins - genetics; Recombinant Proteins - metabolism
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M003807200

Bid is a proapoptotic, BH3-domain-only member of the Bcl-2 family. In Fas-induced apoptosis, Bid is activated through cleavage by caspase 8 into a 15.5-kDa C-terminal fragment (tcBid) and a 6.5 kDa N-terminal fragment (tnBid). Following the cleavage, tcBid translocates to the mitochondria and promotes the release of cytochromec into the cytosol by a mechanism that is not understood. Here we report that recombinant tcBid can act as a membrane destabilizing agent. tcBid induces destabilization and breaking of planar lipid bilayers without appearance of ionic channels; its destabilizing activity is comparable with that of Bax and at least 30-fold higher than that of full-length Bid. Consistently, tcBid, but not full-length Bid, permeabilizes liposomes at physiological pH. The destabilizing effect of tcBid on liposomes and planar bilayers is independent of the BH3 domain. In contrast, mutations in the BH3 domain impair tcBid ability to induce cytochrome c release from mitochondria. The permeabilizing effect of tcBid on planar bilayers, liposomes, and mitochondria can be inhibited by tnBid. In conclusion, our results suggest a dual role for Bid: BH3-independent membrane destabilization and BH3-dependent interaction with other proteins. Moreover, the dissociation of Bid after cleavage by caspase 8 represents an additional step at which apoptosis may be regulated.