Diablo Promotes Apoptosis by Removing Miha/Xiap from Processed Caspase 9

Author:

Ekert Paul G.12,Silke John1,Hawkins Christine J.3,Verhagen Anne M.1,Vaux David L.1

Affiliation:

1. The Walter and Eliza Hall Institute, The Royal Melbourne Hospital, Victoria 3050, Australia

2. Murdoch Children's Research Institute, Royal Children's Hospital, Parkville 3052, Australia

3. Department of Haematology and Oncology, Royal Children's Hospital, Parkville 3052, Australia

Abstract

MIHA is an inhibitor of apoptosis protein (IAP) that can inhibit cell death by direct interaction with caspases, the effector proteases of apoptosis. DIABLO is a mammalian protein that can bind to IAPs and antagonize their antiapoptotic effect, a function analogous to that of the proapoptotic Drosophila molecules, Grim, Reaper, and HID. Here, we show that after UV radiation, MIHA prevented apoptosis by inhibiting caspase 9 and caspase 3 activation. Unlike Bcl-2, MIHA functioned after release of cytochrome c and DIABLO from the mitochondria and was able to bind to both processed caspase 9 and processed caspase 3 to prevent feedback activation of their zymogen forms. Once released into the cytosol, DIABLO bound to MIHA and disrupted its association with processed caspase 9, thereby allowing caspase 9 to activate caspase 3, resulting in apoptosis.

Publisher

Rockefeller University Press

Subject

Cell Biology

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