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Originally published In Press as doi:10.1074/jbc.M003807200 on May 8, 2000

J. Biol. Chem., Vol. 275, Issue 30, 22713-22718, July 28, 2000
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The Destabilization of Lipid Membranes Induced by the C-terminal Fragment of Caspase 8-cleaved Bid Is Inhibited by the N-terminal Fragment*

Grzegorz KudlaDagger , Sylvie MontessuitDagger , Robert EskesDagger §, Catherine Berrier, Jean-Claude MartinouDagger , Alexandre Ghazi, and Bruno AntonssonDagger ||

From the Dagger  Serono Pharmaceutical Research Institute, Serono International S.A., 14, chemin des Aulx, CH-1228 Plan-les Ouates, Geneva, Switzerland and the  Laboratoire des Biomembranes, UMR CNRS 8619, Universite Paris-Sud, 91405 Orsay, France

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 cytochrome c 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.


* The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

§ Present address: J.W.G. University Frankfurt am Main, 60596 Frankfurt, Germany.

|| To whom correspondence should be addressed. Tel.: 41-22-706-9802; Fax: 41-22-794-6965; E-mail: bruno.antonsson.ch_gva03@serono.com.


Copyright © 2000 by The American Society for Biochemistry and Molecular Biology, Inc.
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