A Serine Protease, HtrA2, Is Released From the Mitochondria and Interacts With XIAP, Inducing Cell Death

Mol Cell. 2001 Sep;8(3):613-21. doi: 10.1016/s1097-2765(01)00341-0.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Apoptosis / physiology*
  • Apoptosis Regulatory Proteins
  • Carrier Proteins / metabolism
  • Caspase Inhibitors
  • Caspases / metabolism
  • Cell Fractionation
  • Cell Line
  • Cloning, Molecular
  • Genes, Reporter / genetics
  • High-Temperature Requirement A Serine Peptidase 2
  • Humans
  • Intracellular Signaling Peptides and Proteins
  • Microscopy, Fluorescence
  • Mitochondria / metabolism*
  • Mitochondrial Proteins*
  • Protein Binding
  • Protein Transport / physiology
  • Proteins / metabolism*
  • Recombinant Fusion Proteins / genetics
  • Recombinant Fusion Proteins / metabolism
  • Serine Endopeptidases / chemistry
  • Serine Endopeptidases / genetics
  • Serine Endopeptidases / isolation & purification
  • Serine Endopeptidases / metabolism*
  • Ultraviolet Rays
  • X-Linked Inhibitor of Apoptosis Protein

Substances

  • Apoptosis Regulatory Proteins
  • Carrier Proteins
  • Caspase Inhibitors
  • DIABLO protein, human
  • Intracellular Signaling Peptides and Proteins
  • Mitochondrial Proteins
  • Proteins
  • Recombinant Fusion Proteins
  • X-Linked Inhibitor of Apoptosis Protein
  • XIAP protein, human
  • Serine Endopeptidases
  • HTRA2 protein, human
  • High-Temperature Requirement A Serine Peptidase 2
  • Caspases