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J. Biol. Chem., Vol. 279, Issue 36, 37588-37596, September 3, 2004

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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**, and Hyangshuk Rhim

From the Graduate School of Biotechnology, Korea University, Seoul 136-701, Korea, Research Institute of Molecular Genetics, Catholic Research Institutes of Medical Sciences, Department of Biomedical Sciences, and ^||Department of Biochemistry, College of Medicine, the Catholic University of Korea, Seoul 137-701, Korea, and ^¶Department of Biology, Sangmyung University, Seoul 110-743, Korea

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 glutathione S-transferase-HtrA2/Omi protein. Using N-terminal amino acid sequencing and mutational analysis, we identified that the autocatalytic cleavage site is the carboxyl 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.

Received for publication, February 9, 2004 , and in revised form, May 25, 2004.

^* This work was supported by the Korean Health 21 R&D Project, Ministry of Health and Welfare, Republic of Korea Grant HMP-02-PJ1-PG3-20908-0020, the interdisciplinary research program of Korea Science and Engineering Foundation Grant R01-1999-000-00133-0), and Life Phenomena and Function Research Group Program from Ministry of Science and Technology Grant M1-0016-00-0032. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

^** To whom correspondence may be addressed: Graduate School of Biotechnology, Korea University, Seoul 136-701, Korea. Tel.: 82-2-3290-3448; Fax: 82-2-927-9028; E-mail: skang{at}korea.ac.kr. To whom correspondence may be addressed: Research Institute of Molecular Genetics, Catholic Research Institutes of Medical Science, The Catholic University of Korea, 505 Banpo-dong, Seocho-ku, Seoul 137-701, Korea. Tel.: 82-2-590-2390; Fax: 82-2-532-0575; E-mail: hrhim{at}catholic.ac.kr.

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