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

X chromosome-linked inhibitor of apoptosis (XIAP) is an endogenous inhibitor of caspase-3, -7, and -9. Smac/DIABLO, an inhibitor of XIAP, is released from mitochondria upon receiving apoptotic stimuli and binds to the BIR2 and BIR3 domains of XIAP, thereby inhibiting its caspase-inhibitory activity. Here we report that a serine protease called HtrA2/Omi is released from mitochondria and inhibits the function of XIAP by direct binding in a similar way to Smac. Moreover, when overexpressed extramitochondrially, HtrA2 induces atypical cell death, which is neither accompanied by a significant increase in caspase activity nor inhibited by caspase inhibitors, including XIAP. A catalytically inactive mutant of HtrA2, however, does not induce cell death. In short, HtrA2 is a Smac-like inhibitor of IAP activity with a serine protease-dependent cell death-inducing activity.

Pubmed ID: 11583623

Authors

  • Suzuki Y
  • Imai Y
  • Nakayama H
  • Takahashi K
  • Takio K
  • Takahashi R

Journal

Molecular cell

Publication Data

September 3, 2001

Associated Grants

None

Mesh Terms

  • Amino Acid Sequence
  • Apoptosis
  • Carrier Proteins
  • Caspase Inhibitors
  • Caspases
  • Cell Fractionation
  • Cell Line
  • Cloning, Molecular
  • Genes, Reporter
  • Humans
  • Intracellular Signaling Peptides and Proteins
  • Microscopy, Fluorescence
  • Mitochondria
  • Mitochondrial Proteins
  • Protein Binding
  • Protein Transport
  • Proteins
  • Recombinant Fusion Proteins
  • Serine Endopeptidases
  • Ultraviolet Rays
  • X-Linked Inhibitor of Apoptosis Protein