Figure 1. The intrinsic pathway in C. elegans, D. melanogaster and mammalians. The functional homologues are represented in boxes with the same colour. The activation of effector caspases occurs downstream of the activation of initiator caspases (CED-3, Dronc and caspase-9), which occurs on the formation of the apoptosome, a protein complex contaning CED-4, Ark/Dark and Apaf-1, and cytochrome c. In mammalians, the release of cytochrome c from mitochondria is a critical step for caspase activation, which is regulated by members for the Bcl-2 family of proteins. In Drosophila, the importance of cytochrome c and Bcl-2 family members (Debcl/Buffy) for apoptosome formation and caspase activation is still not clear. In C. elegans, CED-4 directly activates CED-3 with no apparent requirement of cytochrome c for this process to occur. The negative regulation of CED-4 by CED-9 is blocked by EGL-1, a BH3-only member of the Bcl-2 family of proteins. IAPs (in mammalians) or Diap1 (in Drosophila) directly bind to caspases via their BIR (baculovirus inhibitory repeat) domains, to inhibit caspase activity. In Drosophila, reaper, grim and hid are three Diap1 antagonists, which directly bind Diap1 via the short N-terminal peptide motif termed IBM (IAP-binding motif) present in all three proteins, to release caspases from the negative interaction with Diap1. In mammalians, Smac/Diablo, HtrA2/Omi and ARTS (apoptosis-related protein in the TGF-signalling pathway) can function as antagonists of IAPs.