The Apoptotic Protein tBid Promotes Leakage by Altering Membrane Curvature

The apoptotic protein tBid is effective in promoting both leakage and lipid mixing in liposomes composed of cardiolipin and phosphatidylcholine at a molar ratio of 1:2 in the presence of calcium. When half of the phosphatidylcholine component of these liposomes is replaced with phosphatidylethanolamine, a lipid that promotes negative membrane curvature, the rates of both leakage and lipid mixing caused by tBid are substantially increased. Replacement of cardiolipin with phosphatidylglycerol, a lipid that is structurally similar to cardiolipin but does not promote negative membrane curvature in the presence of calcium, prevents the tBid from promoting leakage. The promotion of leakage by tBid is also inhibited by several substances that promote positive membrane curvature, including lysophosphatidylcholine, tritrpticin, a potent antimicrobial peptide, and cyclosporin A, a known inhibitor of cytochrome crelease from mitochondria. We directly measured the effect of tBid on membrane curvature by 31P NMR. We found that tBid promotes the formation of highly curved non-lamellar phases. All of these data are consistent with the hypothesis that tBid promotes negative curvature, and as a result it destabilizes bilayer membranes. Bcl-XL inhibits leakage and lipid mixing induced by tBid. Bcl-XL is anti-apoptotic. It reduces the promotion of non-bilayer phases by tBid, although by itself Bcl-XL is capable of promoting their formation. Bcl-XL has little effect on liposomal integrity. Our results suggest that the anti-apoptotic activity of Bcl-XL is not a consequence of its interaction with membranes, but rather with other proteins, such as tBid. The apoptotic protein tBid is effective in promoting both leakage and lipid mixing in liposomes composed of cardiolipin and phosphatidylcholine at a molar ratio of 1:2 in the presence of calcium. When half of the phosphatidylcholine component of these liposomes is replaced with phosphatidylethanolamine, a lipid that promotes negative membrane curvature, the rates of both leakage and lipid mixing caused by tBid are substantially increased. Replacement of cardiolipin with phosphatidylglycerol, a lipid that is structurally similar to cardiolipin but does not promote negative membrane curvature in the presence of calcium, prevents the tBid from promoting leakage. The promotion of leakage by tBid is also inhibited by several substances that promote positive membrane curvature, including lysophosphatidylcholine, tritrpticin, a potent antimicrobial peptide, and cyclosporin A, a known inhibitor of cytochrome crelease from mitochondria. We directly measured the effect of tBid on membrane curvature by 31P NMR. We found that tBid promotes the formation of highly curved non-lamellar phases. All of these data are consistent with the hypothesis that tBid promotes negative curvature, and as a result it destabilizes bilayer membranes. Bcl-XL inhibits leakage and lipid mixing induced by tBid. Bcl-XL is anti-apoptotic. It reduces the promotion of non-bilayer phases by tBid, although by itself Bcl-XL is capable of promoting their formation. Bcl-XL has little effect on liposomal integrity. Our results suggest that the anti-apoptotic activity of Bcl-XL is not a consequence of its interaction with membranes, but rather with other proteins, such as tBid. phosphatidylcholine phosphatidylethanolamine lysophosphatidylcholine dioleoylphosphatidylcholine dioleoylphosphatidylethanolamine dioleoylphosphatidylglycerol N-(lissamine rhodamine B sulfonyl)phosphatidylethanolamine N-(7-nitro-2,1,3-benzoxadiazol-4-yl)phosphatidylethanolamine large unilamellar vesicle multilamellar vesicle dithiothreitol 8-aminonaphthalene-1,3,6-trisulfonic acid p-xylene-bis-pyridinium bromide The Bcl-2 family of proteins plays an important role in regulating the intracellular apoptotic signal cascade (1Adams J.M. Cory S. Trends Biochem. Sci. 2001; 26: 61-66Abstract Full Text Full Text PDF PubMed Scopus (815) Google Scholar, 2Gross A. McDonnell J.M. Korsmeyer S.J. Genes Dev. 1999; 13: 1899-1911Crossref PubMed Scopus (3268) Google Scholar). Members of this protein family can be either pro-apoptotic, such as tBid, or anti-apoptotic, such as Bcl-XL. Mitochondria play a central role in this process (3Desagher S. Martinou J.C. Trends Cell Biol. 2000; 10: 369-377Abstract Full Text Full Text PDF PubMed Scopus (1696) Google Scholar, 4Martinou J.C. Green D.R. Nat. Rev. Mol. Cell. Biol. 2001; 2: 63-67Crossref PubMed Scopus (851) Google Scholar, 5Ferri K.F. Kroemer G. Nat. Cell Biol. 2001; 3: E255-E263Crossref PubMed Scopus (1306) Google Scholar). A characteristic feature of apoptosis is the rapid and complete release of cytochrome c from the mitochondria into the cytosol (6Madesh M. Antonsson B. Srinivasula S.M. Alnemri E.S. Hajnoczky G. J. Biol. Chem. 2002; 277: 5651-5659Abstract Full Text Full Text PDF PubMed Scopus (157) Google Scholar, 7Goldstein J.C. Waterhouse N.J. Juin P. Evan G.I. Green D.R. Nat. Cell Biol. 2000; 2: 156-162Crossref PubMed Scopus (886) Google Scholar). One of the pro-apoptotic Bcl-2 proteins is Bid. Unlike other Bcl-2 proteins that have several domains, Bid has only one BH3 domain. The proteolytic enzymes, the caspases, also play an important role in apoptosis. One of the roles of caspases-8 is to catalyze the cleavage of Bid to a truncated form, tBid (8Gross A. Yin X.M. Wang K. Wei M.C. Jockel J. Milliman C. Erdjument-Bromage H. Tempst P. Korsmeyer S.J. J. Biol. Chem. 1999; 274: 1156-1163Abstract Full Text Full Text PDF PubMed Scopus (932) Google Scholar, 9Li H. Zhu H., Xu, C.J. Yuan J. Cell. 1998; 94: 491-501Abstract Full Text Full Text PDF PubMed Scopus (3798) Google Scholar, 10Luo X. Budihardjo I. Zou H. Slaughter C. Wang X. Cell. 1998; 94: 481-490Abstract Full Text Full Text PDF PubMed Scopus (3085) Google Scholar). The tBid is then N-myristoylated, which results in its targeting to mitochondria (11Zha J. Weiler S., Oh, K.J. Wei M.C. Korsmeyer S.J. Science. 2000; 290: 1761-1765Crossref PubMed Scopus (477) Google Scholar) where it releases cytochrome c and other proteins from the intermembranous compartment. Cardiolipin is required for the binding of t-Bid to mitochondria (12Lutter M. Fang M. Luo X. Nishijima M. Xie X.S. Wang X.D. Nat. Cell Biol. 2000; 2: 754-756Crossref PubMed Scopus (411) Google Scholar). Several mechanisms have been demonstrated for the action of tBid. It has been shown that tBid can promote the oligomerization of both Bak (13Korsmeyer S.J. Wei M.C. Saito M. Weiler S., Oh, K.J. Schlesinger P.H. Cell Death Differ. 2000; 7: 1166-1173Crossref PubMed Scopus (851) Google Scholar, 14Wei M.C. Lindsten T. Mootha V.K. Weiler S. Gross A. Ashiya M. Thompson C.B. Korsmeyer S.J. Genes Dev. 2000; 14: 2060-2071Crossref PubMed Google Scholar) as well as Bax (15Eskes R. Desagher S. Antonsson B. Martinou J.C. Mol. Cell. Biol. 2000; 20: 929-935Crossref PubMed Scopus (1018) Google Scholar). 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R. C. Martinou J.C. A. Antonsson B. J. Biol. Chem. 2000; Full Text Full Text PDF PubMed Scopus Google Scholar). A of the membrane that to its is the curvature of its 1998; PubMed Scopus Google Scholar). Cell are on a However, of the bilayer have is of curvature be the to to its When a bilayer has a large negative curvature, it from a to an such as the the the are as with an The are with and the are with their to the curvature have in to the of mitochondria. It is known that from a to a in the presence of K. van N. R. B. PubMed Scopus Google Scholar, B. R. A. PubMed Scopus Google Scholar). has also demonstrated the presence of non-bilayer in mitochondria R. PubMed Scopus Google Scholar). The of the membrane to phases has been to the of the membrane P. Biol. PubMed Scopus Google Scholar) as well as the activity of Chem. PubMed Scopus Google Scholar). it is known that cytochrome c itself the formation of the in of cardiolipin B. 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The of Bcl-XL in The a by and from at the of A from All including the from The cardiolipin a and the lysophosphatidylcholine the in at the molar The lipid as a on the of a by with of for in a to a The lipid in the by at to multilamellar The lipid with of and by in a at in and a of leakage from liposomes the H. J. PubMed Scopus Google Scholar). with The of this to be to that of the as measured with a of by as a of the and the by The in of in a at with of to the to a lipid of and the as a of an of and an of with A in the One of the proteins in to the lipid in the to a protein in the of with the of several of a in The of as to only leakage from the The or of leakage caused by the proteins measured several The for leakage by of a to the in The composed of or The of tBid but demonstrated that the effect on leakage at the in the The of D. 20: PubMed Scopus Google Scholar) to membrane either or a of of of these lipid of one and one with of and A molar ratio of to liposomes in the at and of and a the and the with an with in a a and at a lipid of to of in the at and then the protein to a of mixing by of the of The of such that it caused only a of lipid mixing with the The effect of the proteins on the of lipid mixing for several and then of The to of calcium, as The by of the with of lipid mixing at is All in and found to be in that demonstrated that the that in the of tBid effect on lipid mixing at the in the A as by in by at by of and of then into or protein calcium. and then for at by at for at The and for The of by the of by the of Scopus Google Scholar). The of protein by the and of at in a with a with lipid for The 31P measured of a of The lipid as a from a in as for the of The lipid by with in the or presence of tBid Bcl-XL. the lipid at a of to the The then and to and the into a with lipid that effect on the lipid a at in a a in data A of to an of to to by a with a in the of the Mitochondria from have been by as S. A. A. R. Montessuit S. S. K. Antonsson B. Martinou J.C. J. Cell Biol. 1999; PubMed Scopus Google Scholar). Mitochondria of with of in the presence or of tBid for at in of Mitochondria then for at and both the and for cytochrome c by of the an of vesicle is by tBid We have the of leakage from composed of molar with of molar both leakage by the of A that in the of protein the liposomes not but at the the of to that required to leakage in the liposomes without The leakage rates to the lipid tBid potent with liposomes leakage by tBid has recently been shown in in which the of the presence of demonstrated D. X. J. Biochem. 2001; PubMed Scopus Google Scholar). The results be directly with liposomal that not cardiolipin and not The promotion of leakage caused by tBid as a result of with that the in the action of tBid in the presence of be a consequence of the that this lipid promotes negative this substances that positive membrane curvature and be to the action of tBid. We tritrpticin, cyclosporin A, and substances of of which promote positive membrane One of these tritrpticin, an antimicrobial W. Biochem. Cell Biol. 2002; PubMed Scopus Google and the lipid PubMed Scopus Google Scholar, A. Green J. J. J. Full Text PDF PubMed Scopus Google Scholar). of these substances to of or to a of of the of and tBid the to the data of leakage a of or of the the We also cyclosporin A, an that inhibits negative curvature J. Biol. Chem. Full Text PDF PubMed Google Scholar). a of this inhibited leakage from several positive curvature the action of tBid. Cardiolipin non-lamellar in the presence of but dioleoylphosphatidylglycerol does We for cardiolipin in liposomes with or leakage is inhibited is for One of the for the in activity of tBid with of lipid be a consequence of of binding to these liposomal binding of tBid to lipid to the and an of protein to be to the protein that in the We that in the presence of half of the tBid to of either or The in the binding these lipid the in leakage rates with liposomes of the lipid cardiolipin with the binding of tBid to the liposomes the of leakage activity of tBid with liposomes is not a consequence of the of the protein to We have also of and anti-apoptotic Bcl-2 proteins on liposomal leakage. Bcl-XL has little effect on leakage from liposomes of from liposomes of of is a large of the leakage induced by tBid the of Bcl-XL with lipid mixing is by tBid liposomes cardiolipin in the presence of as with lipid mixing by tBid is liposomes of with of However, the to lipid is with lipid mixing with leakage with leakage is a large of the lipid mixing induced by tBid with the of Bcl-XL of lipid mixing from liposomes composed of with of lipid mixing by tBid Bcl-XL tBid Bcl-XL and The and of a lipid can be by 31P NMR. It is known that the of promote the A. J. J. 1999; Full Text Full Text PDF PubMed Scopus Google Scholar) and membrane J. S. J. D. PubMed Scopus Google Scholar, J. M. R. 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Cell Biol. 2002; PubMed Scopus Google for its to cytochrome c Mitochondria from in these Bax shown to be to mitochondria from these their of tBid to mitochondria from results in Bax and oligomerization and to release (15Eskes R. Desagher S. Antonsson B. Martinou J.C. Mol. Cell. Biol. 2000; 20: 929-935Crossref PubMed Scopus (1018) Google Scholar). at from to for its to the action of with the of or to mitochondria to a release of cytochrome is known to have potent activity W. Biochem. Cell Biol. 2002; PubMed Scopus Google Scholar). with other of its at it is to liposomes H. J. and R. M. as well as to mitochondria. However, at release of cytochrome c from mitochondria of tBid to mitochondria by effect inhibited by the of are several results that suggest that of membrane by the negative curvature of the membrane apoptosis. promotes negative curvature in cardiolipin S. PubMed Scopus Google Scholar). pro-apoptotic Bcl-2 proteins the of into the mitochondria A. J. Fang B. J. J. Biol. 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Chem. 2002; 277: 5651-5659Abstract Full Text Full Text PDF PubMed Scopus (157) Google Scholar). is also consistent with the protein is negative curvature in the A, an inhibitor of negative curvature in J. Biol. Chem. Full Text PDF PubMed Google inhibits apoptosis Ashiya M. K. Weiler S. Korsmeyer S.J. Dev. Cell. 2002; 2: Full Text Full Text PDF PubMed Scopus Google Scholar). are well known as of apoptosis PubMed Scopus Google Scholar, M. T. M. 2000; PubMed Scopus Google Scholar, P. M. S. C. J. Biol. Chem. 1999; 274: Full Text Full Text PDF PubMed Scopus Google Scholar) and these promote negative curvature A. J. Biol. Chem. 2002; 277: Full Text Full Text PDF PubMed Scopus Google Scholar). this several of to that tBid can this at in a consequence of tBid promoting negative curvature in membrane with this leakage of liposomal by tBid is rapid from with negative curvature, in which is for half of the is also the for lipid although with to lipid structurally tritrpticin, cyclosporin A, and which promote positive curvature, liposomal leakage by tBid. of cardiolipin by prevents leakage induced by tBid is also in with curvature cardiolipin negative curvature in the presence of does that tBid promotes the formation of a highly curved non-bilayer the with lipid both as a of as well as of tBid to the action of tBid (17Grinberg M. Sarig R. Zaltsman Y. Frumkin D. Grammatikakis N. Reuveny E. Gross A. J. Biol. Chem. 2002; 277: 12237-12245Abstract Full Text Full Text PDF PubMed Scopus (133) Google tBid can also the oligomerization of other Bcl-2 It has also been shown that tBid promotes the oligomerization of Bax (15Eskes R. Desagher S. Antonsson B. Martinou J.C. Mol. Cell. Biol. 2000; 20: 929-935Crossref PubMed Scopus (1018) Google Scholar). is that in Bax be with tBid to promote apoptosis. Bax in the of Bid M. Gross A. Korsmeyer H. Yuan J. Cell Death Differ. 2000; 7: PubMed Scopus Google Scholar) tBid in the of Bax M.C. Lindsten T. Thompson C.B. Korsmeyer S.J. Science. 2001; PubMed Scopus Google Scholar) can apoptosis in However, in with Bax the release of of the presence of tBid and Bax and tBid Y. Yin X.M. J. Biol. Chem. 2000; Full Text Full Text PDF PubMed Scopus Google Scholar). can be in of the of tBid in the the that is by Bax A. J. Fang B. J. J. Biol. Chem. 2002; 277: Full Text Full Text PDF PubMed Scopus Google Scholar, J. A. Fang B. J. Biol. Chem. 2002; 277: Full Text Full Text PDF PubMed Scopus Google Scholar). the tBid and to the mitochondria (11Zha J. Weiler S., Oh, K.J. Wei M.C. Korsmeyer S.J. Science. 2000; 290: 1761-1765Crossref PubMed Scopus (477) Google Scholar). to its action in promoting of to the Bax also directly to the mitochondria and also have on this as are to also be one by which of the pro-apoptotic proteins are mechanisms by which the can leakage of cytochrome c from mitochondria. One is by a of the action of tBid on mitochondria and the other is of oligomerization of either the results the that membrane curvature the apoptotic action of tBid. is that the anti-apoptotic also with Bcl-2 proteins a BH3 M. H. D. M. Thompson C.B. Science. PubMed Scopus Google Scholar). with Bcl-XL inhibits both leakage and lipid mixing by tBid. protein also inhibits the promotion of the formation by tBid However, by Bcl-XL is capable of promoting the formation of the not be for a protein that is anti-apoptotic and does not promote vesicle leakage or lipid Bcl-XL the that the Bcl-2 proteins into the membrane of the mitochondria. However, at and of into the membrane as a result of a It has been shown that of Bcl-XL can membrane leakage G. J. G.I. J. J.M. J. J. Biol. Chem. 2001; 276: Full Text Full Text PDF PubMed Scopus Google Scholar). It is that the of Bcl-XL for this can into to promote formation of the The of Bcl-XL to the action of tBid be a consequence of interaction tBid M. H. D. M. Thompson C.B. Science. PubMed Scopus Google rather of membrane that tBid negative curvature in and promotes the formation of non-bilayer phases. curvature is well with the of tBid to membrane both with to the promotion of liposomal leakage by as well as its by tritrpticin, cyclosporin A, and The bilayer caused by tBid is by the in the which is known to promote negative curvature with cardiolipin and to apoptosis. directly 31P the effect of tBid on lipid tBid also with other Bcl-2 is a process in which several proteins and into this that the of the membrane also play an important role in this We are for the of Montessuit in the of the

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