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Activation of Apoptosis by Cytoplasmic Microinjection of Cytochrome c
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Activation of Apoptosis by Cytoplasmic Microinjection of Cytochrome c

Published on: June 29, 2011

A serine protease, HtrA2, is released from the mitochondria and interacts with XIAP, inducing cell death

Y Suzuki1, Y Imai, H Nakayama

  • 1Laboratory for Motor System Neurodegeneration, Brain Science Institute, Wako City, Saitama 351-0198, Japan.

Molecular Cell
|October 5, 2001
PubMed

Insights

HtrA2/Omi, a mitochondrial serine protease, inhibits X chromosome-linked inhibitor of apoptosis (XIAP) function by binding. HtrA2 also induces atypical cell death independent of caspase activity.

Area of Science:

  • Molecular Biology
  • Cell Death Pathways

Background:

  • The X chromosome-linked inhibitor of apoptosis (XIAP) protein suppresses apoptosis by inhibiting caspases-3, -7, and -9.
  • Mitochondria-released Smac/DIABLO antagonizes XIAP by binding to its BIR2 and BIR3 domains.

Purpose of the Study:

  • To investigate the role of the mitochondrial serine protease HtrA2/Omi in regulating XIAP function and inducing cell death.
  • To determine if HtrA2/Omi acts as a Smac/DIABLO-like inhibitor of XIAP.

Main Methods:

  • Investigated HtrA2/Omi release from mitochondria upon apoptotic stimuli.
  • Assessed HtrA2/Omi binding to XIAP.
  • Studied the effect of extramitochondrial HtrA2/Omi overexpression on cell death induction.
  • Utilized catalytically inactive HtrA2/Omi mutants to assess protease activity dependence.

Main Results:

  • HtrA2/Omi is released from mitochondria and directly binds to XIAP, inhibiting its function similarly to Smac/DIABLO.
  • Extramitochondrial HtrA2/Omi overexpression induces atypical cell death, independent of caspase activation and resistant to XIAP.
  • A catalytically inactive HtrA2/Omi mutant failed to induce cell death, highlighting the requirement of its protease activity.

Conclusions:

  • HtrA2/Omi functions as a Smac/DIABLO-like inhibitor of XIAP, antagonizing its anti-apoptotic activity.
  • HtrA2/Omi possesses a distinct serine protease-dependent cell death-inducing activity, separate from its XIAP inhibitory function.

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