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The serine protease Omi/HtrA2 regulates apoptosis by binding XIAP through a reaper-like motif

L Miguel Martins1, Ingram Iaccarino, Tencho Tenev

  • 1Imperial Cancer Research Fund, 44 Lincoln's Inn Fields, London WC2A 3PX, United Kingdom.

The Journal of Biological Chemistry
|October 17, 2001
PubMed

Insights

The serine protease Omi/HtrA2 binds to XIAP, promoting apoptosis. Released from mitochondria during cell death, Omi/HtrA2 acts as a Reaper-like protein, sensitizing cells and reducing caspase inhibition.

Area of Science:

  • Cell Biology
  • Molecular Biology
  • Biochemistry

Background:

  • Inhibitor-of-apoptosis proteins (IAPs) regulate programmed cell death by inhibiting caspases.
  • Reaper proteins and Smac/DIABLO promote apoptosis by binding IAPs.
  • Understanding IAP regulation is crucial for controlling cell death pathways.

Purpose of the Study:

  • To identify novel mammalian proteins that interact with IAPs and modulate apoptosis.
  • To characterize the role of the serine protease Omi/HtrA2 in apoptosis regulation.
  • To elucidate the mechanism by which Omi/HtrA2 influences caspase activity.

Main Methods:

  • Yeast two-hybrid screening to identify XIAP-binding proteins.
  • Western blotting and immunoprecipitation to confirm protein interactions.
  • Confocal microscopy to determine subcellular localization.
  • RNA interference (RNAi) to assess the functional role of Omi/HtrA2.
  • Overexpression studies to evaluate Omi/HtrA2's impact on apoptosis.

Main Results:

  • Omi/HtrA2 was identified as a novel XIAP-binding protein with a Reaper-like motif.
  • Full-length Omi/HtrA2 localizes to mitochondria, while processed Omi/HtrA2 translocates to the cytosol upon apoptotic stimulus.
  • Processed Omi/HtrA2 interacts with XIAP in the cytosol, blocking its caspase-inhibitory function.
  • Overexpression of Omi/HtrA2 enhances apoptosis, whereas its depletion reduces cell death.

Conclusions:

  • Omi/HtrA2 is a second mammalian protein, alongside Smac/DIABLO, that antagonizes IAP function.
  • Omi/HtrA2 is released from mitochondria during apoptosis and promotes cell death by interacting with XIAP.
  • These findings expand the known repertoire of mitochondrial proteins that regulate apoptosis through IAP antagonism.

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