Direct addition of BimL to mitochondria does not lead to cytochrome c release.
Pro-apoptotic members of the Bcl-2 family can be subdivided in two classes according to their structure: a group including Bax, Bak, and Bok that display Bcl-2 homology (BH) 1, BH2 and BH3 domains and a second group including Bid (BH3 interacting domain death agonist), Bad, Bim (Bcl-2 interacting mediator of cell death) and several others that contain only a BH3 domain, the BH3-only proteins. The BH3-only proteins have been proposed to activate pro-apoptotic members of the Bax subfamily to trigger a mitochondrial pathway that leads to the release of cytochrome c and other apoptogenic factors. Here we report that the mechanism of action of Bim is different from that of Bid. Although overexpression of Bid or Bim in cells leads to cytochrome c release, only Bid is able to trigger the release of cytochrome c through Bax activation when added directly to isolated mitochondria. Bim(L), although unable to activate Bax, can directly inhibit Bcl-2 or Bcl-x(L). Our data suggest two functional classes of BH3-only proteins: those such as Bid which directly activate Bax-like proteins leading to mitochondrial membrane permeability and apoptosis and those such as Bim which inhibit anti-apoptotic proteins and render the cells more susceptible to apoptogenic stimuli.
Terradillos
Olivier
O
Département de Biologie Cellulaire, Sciences III, 30 quai E. Ansermet, 1211 Genève 4, Switzerland.
Montessuit
Sylvie
S
Huang
David C S
DC
Martinou
Jean-Claude
JC
D000818:Animals; D051017:Apoptosis Regulatory Proteins; D051023:BH3 Interacting Domain Death Agonist Protein; D000072224:Bcl-2-Like Protein 11; D002352:Carrier Proteins / Q000235:genetics / Q000302:isolation & purification / Q000378:metabolism / Q000494:pharmacology*; D002462:Cell Membrane / Q000378:metabolism; D003574:Cytochrome c Group / Q000378:metabolism*; D006367:HeLa Cells; D006801:Humans; D008565:Membrane Proteins; D051379:Mice; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics / Q000378:metabolism*; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000302:isolation & purification / Q000494:pharmacology; D051028:bcl-2-Associated X Protein
D051017:Apoptosis Regulatory Proteins; C494826:BAX protein, human; C000606775:BCL2L11 protein, human; D051023:BH3 Interacting Domain Death Agonist Protein; C494814:BID protein, human; C494827:Bax protein, mouse; D000072224:Bcl-2-Like Protein 11; C000606776:Bcl2l11 protein, mouse; C494815:Bid protein, mouse; D002352:Carrier Proteins; D003574:Cytochrome c Group; D008565:Membrane Proteins; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D011993:Recombinant Fusion Proteins; D051028:bcl-2-Associated X Protein