Pro-apoptotic Bid induces membrane perturbation by inserting selected lysolipids into the bilayer.
Bid is a BH3-only member of the Bcl-2 family that regulates cell death at the level of mitochondrial membranes. Bid appears to link the mitochondrial pathway with the death receptor-mediated pathway of cell death. It is generally assumed that the f.l. (full-length) protein becomes activated after proteolytic cleavage, especially by apical caspases like caspase 8. The cleaved protein then relocates to mitochondria and promotes membrane permeabilization, presumably by interaction with mitochondrial lipids and other Bcl-2 proteins that facilitate the release of apoptogenic proteins like cytochrome c. Although the major action may reside in the C-terminus part, tBid (cleaved Bid), un-cleaved Bid also has pro-apoptotic potential when ectopically expressed in cells or in vitro. This pro-apoptotic action of f.l. Bid has remained unexplained, especially at the biochemical level. In the present study, we show that f.l. (full-length) Bid can insert specific lysolipids into the membrane surface, thereby priming mitochondria for the release of apoptogenic factors. This is most effective for lysophosphatidylcholine species that we report to accumulate in mitochondria during apoptosis induction. A Bid mutant that is not pro-apoptotic in vivo is defective in lysophosphatidylcholine-mediated membrane perturbation in vitro. Our results thus provide a biochemical explanation for the pro-apoptotic action of f.l. Bid.
Goonesinghe
Alexander
A
School of Biological Sciences, The University of Manchester, Stopford Building, Oxford Road, Manchester M13 9PT, UK.
Mundy
Elizabeth S
ES
Smith
Melanie
M
Khosravi-Far
Roya
R
Martinou
Jean-Claude
JC
Esposti
Mauro D
MD
D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D051023:BH3 Interacting Domain Death Agonist Protein; D002308:Cardiolipins / Q000378:metabolism; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000378:metabolism*; D006801:Humans; D019169:Jurkat Cells / Q000378:metabolism; D008051:Lipid Bilayers / Q000378:metabolism*; D008244:Lysophosphatidylcholines / Q000378:metabolism*; D008297:Male; D013058:Mass Spectrometry / Q000379:methods; D051379:Mice; D008928:Mitochondria / Q000378:metabolism; D008930:Mitochondria, Liver / Q000378:metabolism; D009154:Mutation / Q000235:genetics / Q000502:physiology
D051023:BH3 Interacting Domain Death Agonist Protein; C494814:BID protein, human; C494815:Bid protein, mouse; D002308:Cardiolipins; D002352:Carrier Proteins; D008051:Lipid Bilayers; D008244:Lysophosphatidylcholines