Fig. 1. Models of apoptosome regulation. (A) In vertebrate cells, a variety of apoptotic stimuli induce release of cytochrome c from the mitochondria. Once released, cytochrome c binds to Apaf-1, promoting a conformational change that leads to the exposure of the CARD domain and consequent recruitment of pro-caspase-9 into the active oligomerized apoptosome; caspase-9 can then cleave and activate effector caspases. Cytochrome c release from the mitochondria is promoted by pro-apoptotic Bcl-2-family members such as Bax and Bak and is antagonized by anti-apoptotic members of the family such as Bcl-2 and Bcl-x_L. Red rectangles, Apaf-1; light-blue circles, caspase-9; green stars, cytochrome c. (B) In Drosophila cells, it is possible that cytochrome c, or some other intramitochondrial factor (represented here by brown triangles) is released from mitochondria in response to apoptotic stimuli, to promote the activation of the Dark/Dronc apoptosome (red rectangles and blue circles, respectively). This might stimulate oligomerization or enhance activation of the already oligomerized structure. (C) If the fly Bcl-2-family members do not act at the level of cytochrome c release from the mitochondria as in vertebrates, it is possible that pro-apoptotic Debcl protein (yellow rectangles) interacts in some way with the apoptosome to promote its activation. (D) By analogy to the worm system, it is possible that the anti-apoptotic Bcl-2-family protein, Buffy, binds to and inhibits the apoptosome (either at the mitochondrial surface or elsewhere). One possible scenario is that pro-apoptotic Debcl facilitates apoptosome activation by dimerizing with and thereby removing Buffy from the apoptosome. (E) The C. elegans apoptosome is held in check by binding of Ced-9 to Ced-4. This repression is relieved following Egl-1 production and interaction with Ced-9. Red bars, Ced-4; light-blue circles, Ced-3.