DIABLO promotes apoptosis by removing MIHA/XIAP from processed caspase 9

J Cell Biol. 2001 Feb 5;152(3):483-90. doi: 10.1083/jcb.152.3.483.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Apoptosis Regulatory Proteins
  • Apoptosis* / drug effects
  • Apoptosis* / radiation effects
  • Apoptotic Protease-Activating Factor 1
  • Blotting, Western
  • Carrier Proteins / metabolism*
  • Caspase 3
  • Caspase 9
  • Caspases / metabolism*
  • Cell Line
  • Culture Media, Serum-Free
  • Enzyme Activation
  • Enzyme Inhibitors / pharmacology*
  • Flow Cytometry
  • Humans
  • Intracellular Signaling Peptides and Proteins
  • Mitochondrial Proteins*
  • Precipitin Tests
  • Protein Precursors / metabolism
  • Proteins / metabolism
  • Proteins / pharmacology*
  • Proto-Oncogene Proteins c-bcl-2 / metabolism
  • Saccharomyces cerevisiae / genetics
  • Saccharomyces cerevisiae / metabolism
  • Transfection
  • Ultraviolet Rays
  • X-Linked Inhibitor of Apoptosis Protein

Substances

  • APAF1 protein, human
  • Apoptosis Regulatory Proteins
  • Apoptotic Protease-Activating Factor 1
  • Carrier Proteins
  • Culture Media, Serum-Free
  • DIABLO protein, human
  • Enzyme Inhibitors
  • Intracellular Signaling Peptides and Proteins
  • Mitochondrial Proteins
  • Protein Precursors
  • Proteins
  • Proto-Oncogene Proteins c-bcl-2
  • X-Linked Inhibitor of Apoptosis Protein
  • XIAP protein, human
  • CASP3 protein, human
  • CASP9 protein, human
  • Caspase 3
  • Caspase 9
  • Caspases