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

Young Mo Seong, Ju Youn Choi, Hyo Jin Park, Ki Joong Kim, Sang Gun Ahn, Geun Hye Seong, In Kyung Kim, Seongman Kang, Hyangshuk Rhim

Research output: Contribution to journalArticle

35 Citations (Scopus)

Abstract

A mature form of nuclear-encoded mitochondrial serine protease HtrA2/Omi is pivotal in regulating apoptotic cell death; however, the underlying mechanism of the processing event of HtrA2/Omi and its relevant biological function remain to be clarified. Here, we describe that HtrA2/Omi is autocatalytically processed to the 36-kDa protein fragment, which is required for the cytochrome c-dependent caspase activation along with neutralizing XIAP-mediated inhibition of caspases through interaction with XIAP, eventually promoting apoptotic cell death. We have shown that the autocatalytic processing of HtrA2/Omi occurs via an intermolecular event, demonstrated by incubating an in vitro translated HtrA2/Omi (S306A) mutant with the enzymatically active gluatathione S-transferase-HtrA2/Omi protein. Using N-terminal amino acid sequencing and mutational analysis, we identified that the autocatalytic cleavage site is the carbosyl side of alanine 133 of HtrA2/ Omi, resulting in exposure of an inhibitor of apoptosis protein binding motif in its N terminus. Our study provides evidence that the autocatalytic processing of HtrA2/Omi is crucial for regulating HtrA2/Omi-mediated apoptotic cell death.

Original languageEnglish
Pages (from-to)37588-37596
Number of pages9
JournalJournal of Biological Chemistry
Volume279
Issue number36
DOIs
Publication statusPublished - 2004 Sep 3

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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