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J. Biol. Chem., Vol. 279, Issue 45, 46566-46572, November 5, 2004

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Omi/HtrA2 Promotes Cell Death by Binding and Degrading the Anti-apoptotic Protein ped/pea-15^*

Alessandra Trencia, Francesca Fiory, Maria Alessandra Maitan, Pasquale Vito¶, Alessia Paola Maria Barbagallo, Anna Perfetti, Claudia Miele, Paola Ungaro, Francesco Oriente, Lucia Cilenti||, Antonis S. Zervos||, Pietro Formisano, and Francesco Beguinot**

From the Dipartimento di Biologia e Patologia Cellulare e Molecolare and Istituto di Endocrinologia ed Oncologia Sperimentale del CNR, Università degli Studi di Napoli Federico II, Naples 80131, Italy, the ^¶Dipartimento di Scienze Biologiche ed Ambientali, Università degli Studi del Sannio, Benevento 82100, Italy, and the ^||Department of Molecular Biology and Microbiology, University of Central Florida, Orlando, Florida 32826

ped/pea-15 is a ubiquitously expressed 15-kDa protein featuring a broad anti-apoptotic function. In a yeast two-hybrid screen, the pro-apoptotic Omi/HtrA2 mitochondrial serine protease was identified as a specific interactor of the ped/pea-15 death effector domain. Omi/HtrA2 also bound recombinant ped/pea-15 in vitro and co-precipitated with ped/pea-15 in 293 and HeLa cell extracts. In these cells, the binding of Omi/HtrA2 to ped/pea-15 was induced by UVC exposure and followed the mitochondrial release of Omi/HtrA2 into the cytoplasm. Upon UVC exposure, cellular ped/pea-15 protein expression levels decreased. This effect was prevented by the ucf-101 specific inhibitor of the Omi/HtrA2 proteolytic activity, in a dose-dependent fashion. In vitro incubation of ped/pea-15 with Omi/HtrA2 resulted in ped/pea-15 degradation. In intact cells, the inhibitory action of ped/pea-15 on UVC-induced apoptosis progressively declined at increasing Omi/HtrA2 expression. This further effect of Omi/HtrA2 was also inhibited by ucf-101. In addition, ped/pea-15 expression blocked Omi/HtrA2 co-precipitation with the caspase inhibitor protein XIAP and caspase 3 activation. Thus, in part, apoptosis following Omi/HtrA2 mitochondrial release is mediated by reduction in ped/pea-15 cellular levels. The ability of Omi/HtrA2 to relieve XIAP inhibition on caspases is modulated by the relative levels of Omi/HtrA2 and ped/pea-15.

Received for publication, June 7, 2004 , and in revised form, August 2, 2004.

^* This work was supported in part by the European Community (EUDG and EUGENE2 programs), grants from the Associazione Italiana per la Ricerca sul Cancro (AIRC) (to F. B. and P. F.), the Ministero dell'Università e della Ricerca Scientifica (PRIN (to F. B. and P. F.)) and FIRB RBNE0155LB), and Telethon-Italy. 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.

Recipients of fellowships of the Federazione Italiana per la Ricerca sul Cancro.

^** To whom correspondence should be addressed: Dipartimento di Biologia e Patologia Cellulare e Molecolare, Università di Napoli Federico II, Via Sergio Pansini, 5, Naples 80131, Italy. E-mail: beguino{at}unina.it.

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