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Autocatalytic processing of HtrA2/Omi is essential for induction of caspase-dependent cell death through antagonizing

Young-Mo Seong1, Ju-Youn Choi, Hyo-Jin Park

  • 1Graduate School of Biotechnology, Korea University, Seoul 136-701, Korea.

The Journal of Biological Chemistry
|June 18, 2004
PubMed

Insights

The mitochondrial serine protease HtrA2/Omi is processed to a 36-kDa fragment, crucial for apoptosis regulation. This fragment activates caspases and neutralizes XIAP, promoting programmed cell death.

Area of Science:

  • Cell Biology
  • Biochemistry
  • Molecular Biology

Background:

  • Nuclear-encoded mitochondrial serine protease HtrA2/Omi regulates apoptotic cell death.
  • The precise mechanism of HtrA2/Omi processing and its biological role require further elucidation.

Purpose of the Study:

  • To investigate the autocatalytic processing of HtrA2/Omi.
  • To determine the role of the processed HtrA2/Omi fragment in apoptosis and caspase activation.

Main Methods:

  • In vitro translation and incubation of HtrA2/Omi (S306A) mutant with active GST-HtrA2/Omi.
  • N-terminal amino acid sequencing.
  • Mutational analysis to identify cleavage sites.

Main Results:

  • HtrA2/Omi undergoes autocatalytic processing to a 36-kDa fragment, essential for cytochrome c-dependent caspase activation.
  • The processed HtrA2/Omi fragment interacts with XIAP, neutralizing its caspase-inhibitory function.
  • Autocatalytic cleavage occurs intermolecularly at the carboxyl side of alanine 133, exposing an XIAP-binding motif.

Conclusions:

  • Autocatalytic processing of HtrA2/Omi is a critical regulatory step in initiating apoptotic cell death.
  • The 36-kDa processed fragment of HtrA2/Omi plays a key role in promoting apoptosis by activating caspases and overcoming XIAP inhibition.

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