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J. Biol. Chem., Vol. 279, Issue 48, 50295-50301, November 26, 2004

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Regulation of HAX-1 Anti-apoptotic Protein by Omi/HtrA2 Protease during Cell Death^*

Lucia Cilenti, Mangala M. Soundarapandian, George A. Kyriazis, Valerie Stratico, Supriya Singh, Sanjeev Gupta, Joseph V. Bonventre¶, Emad S. Alnemri, and Antonis S. Zervos||

From the Biomolecular Science Center, Burnett College of Biomedical Sciences, University of Central Florida, Orlando, Florida 32826, Center of Apoptosis Research and Department of Microbiology and Immunology, Kimmel Cancer Institute, Thomas Jefferson University, Philadelphia, Pennsylvania 19107, and ^¶Renal Division, Brigham and Women's Hospital/Harvard Medical School, Boston, Massachusetts 02115

Omi/HtrA2 is a nuclear-encoded mitochondrial serine protease that has a pro-apoptotic function in mammalian cells. Upon induction of apoptosis, Omi translocates to the cytoplasm and participates in caspase-dependent apoptosis by binding and degrading inhibitor of apoptosis proteins. Omi can also initiate caspase-independent apoptosis in a process that relies entirely on its ability to function as an active protease. To investigate the mechanism of Omi-induced apoptosis, we set out to isolate novel substrates that are cleaved by this protease. We identified HS1-associated protein X-1 (HAX-1), a mitochondrial anti-apoptotic protein, as a specific Omi interactor that is cleaved by Omi both in vitro and in vivo. HAX-1 degradation follows Omi activation in cells treated with various apoptotic stimuli. Using a specific inhibitor of Omi, HAX-1 degradation is prevented and cell death is reduced. Cleavage of HAX-1 was not observed in a cell line derived from motor neuron degeneration 2 mice that carry a mutated form of Omi that affects its proteolytic activity. Degradation of HAX-1 is an early event in the apoptotic process and occurs while Omi is still confined in the mitochondria. Our results suggest that Omi has a unique pro-apoptotic function in mitochondria that involves removal of the HAX-1 anti-apoptotic protein. This function is distinct from its ability to activate caspase-dependent apoptosis in the cytoplasm by degrading inhibitor of apoptosis proteins.

Received for publication, May 28, 2004 , and in revised form, September 9, 2004.

^* This work was supported by National Institutes of Health Grant R01 DK55734-01 (to A. S. Z.). 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 should be addressed: Biomolecular Science Center, Burnett College of Biomedical Sciences, University of Central Florida, 12722 Research Pkwy., Orlando, FL 32826. Tel.: 407-882-2263; Fax: 407-384-2062; E-mail: azervos{at}mail.ucf.edu.

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