The Drosophila caspase DRONC cleaves following glutamate or aspartate and is regulated by DIAP1, HID, and GRIM

The caspase family of cysteine proteases plays important roles in bringing about apoptotic cell death. All caspases studied to date cleave substrates COOH-terminal to an aspartate, Here we show that the Drosophila caspase DRO NC cleaves COOH-terminal to glutamate as well as aspartate, DRONC autoproce sses itself following a glutamate residue, but processes a second caspase, drICE, following an aspartate, DRONC prefers tetrapeptide substrates in whi ch aliphatic amino acids are present at the P2 position, and the P1 residue can be either aspartate or glutamate, Expression of a dominant negative fo rm of DRONC blocks cell death induced by the Drosophila cell death activato rs reaper, hid, and grim, and DRONC overexpression in flies promotes cell d eath. Furthermore, the Drosophila cell death inhibitor DIAP1 inhibits DRONC activity in yeast, and DIAP1's ability to inhibit DRONC-dependent yeast ce ll death is suppressed by HID and GRIM. These observations suggest that DRO NC acts to promote cell death. However, DRONC activity is not suppressed by the caspase inhibitor and cell death suppressor baculovirus p35. We discus s possible models for DRONC function as a cell death inhibitor.