The Drosophila inhibitor of apoptosis D-IAP1 suppresses cell death induced by the caspase drICE.

Many members of the Inhibitor of Apoptosis (IAP) family inhibit cell death and existing data suggest at least two mechanisms of action. Drosophila IAPs (D-IAP1 and D-IAP2) and a baculovirus-derived IAP, Op-IAP, physically interact with and inhibit the anti-apoptotic activity of Reaper, HID, and Grim, three genetically defined inducers of apoptosis in Drosophila, while human IAPs, c-IAP1, c-IAP2, and X-IAP interact with a number of different proteins including specific members of the caspase family of cysteine proteases which are crucial in the execution of cell death. We have examined whether insect-active IAPs can inhibit apoptosis induced by selected caspases, Drosophila drICE, Sf-caspase-1, and mammalian caspase-3, in insect SF-21 cells. D-IAP1 inhibited apoptosis induced by the active forms of all three caspases tested and physically interacted with the active, but not the proform of drICE. MIHA, the mouse homolog of X-IAP and an effective inhibitor of caspase-3, also interacted with and blocked apoptosis induced by active drICE but was relatively ineffective in blocking Sf-caspase-1. Op-IAP and D-IAP2 were unable to inhibit effectively any of the active caspases tested and failed to interact with drICE. The Drosophila IAPs and Op-IAP, but not MIHA, blocked HID-initiated activation of pro-drICE. We conclude that D-IAP1 is capable of inhibiting the activation of drICE as well as inhibiting apoptosis induced by the active form of drICE. In contrast, D-IAP2 and Op-IAP are more limited in their inhibitory targets and may be limited to inhibiting the activation of caspases.