title: DIABLO promotes apoptosis by removing MIHA/XIAP from processed caspase 9.
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.
authors.affiliation: The Walter and Eliza Hall Institute, The Royal Melbourne Hospital, Victoria 3050, Australia.
authors.forename: P G
authors.initials: PG
authors.lastname: Ekert
authors.forename: J
authors.initials: J
authors.lastname: Silke
authors.forename: C J
authors.initials: CJ
authors.lastname: Hawkins
authors.forename: A M
authors.initials: AM
authors.lastname: Verhagen
authors.forename: D L
authors.initials: DL
authors.lastname: Vaux
mesh_terms: D017209:Apoptosis / Q000187:drug effects / Q000528:radiation effects; D051017:Apoptosis Regulatory Proteins; D053477:Apoptotic Protease-Activating Factor 1; D015153:Blotting, Western; D002352:Carrier Proteins / Q000378:metabolism*; D053148:Caspase 3; D053453:Caspase 9; D020169:Caspases / Q000378:metabolism*; D002460:Cell Line; D016895:Culture Media, Serum-Free; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005434:Flow Cytometry; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D024101:Mitochondrial Proteins; D011233:Precipitin Tests; D011498:Protein Precursors / Q000378:metabolism; D011506:Proteins / Q000378:metabolism / Q000494:pharmacology*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D012441:Saccharomyces cerevisiae / Q000235:genetics / Q000378:metabolism; D014162:Transfection; D014466:Ultraviolet Rays; D051636:X-Linked Inhibitor of Apoptosis Protein
chemical_list: C506592:APAF1 protein, human; D051017:Apoptosis Regulatory Proteins; D053477:Apoptotic Protease-Activating Factor 1; D002352:Carrier Proteins; D016895:Culture Media, Serum-Free; C412403:DIABLO protein, human; D004791:Enzyme Inhibitors; D047908:Intracellular Signaling Peptides and Proteins; D024101:Mitochondrial Proteins; D011498:Protein Precursors; D011506:Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D051636:X-Linked Inhibitor of Apoptosis Protein; C496866:XIAP protein, human; C505407:CASP3 protein, human; C506433:CASP9 protein, human; D053148:Caspase 3; D053453:Caspase 9; D020169:Caspases