Authors

A. Trencia; F. Fiory; M. A. Maitan; P. Vito; A. P. M. Barbagallo; A. Perfetti; C. Miele; P. Ungaro; F. Oriente; L. Cilenti; A. S. Zervos; P. Formisano;F. Beguinot

Comments

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Abbreviated Journal Title

J. Biol. Chem.

Keywords

SERINE-PROTEASE; GLUCOSE-TRANSPORT; CASPASE ACTIVITY; STRUCTURAL BASIS; OUTER-MEMBRANE; KINASE; MITOCHONDRIA; XIAP; INHIBITOR; SMAC/DIABLO; Biochemistry & Molecular Biology

Abstract

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.

Journal Title

Journal of Biological Chemistry

Volume

279

Issue/Number

45

Publication Date

1-1-2004

Document Type

Article

Language

English

First Page

46566

Last Page

46572

WOS Identifier

WOS:000224832400029

ISSN

0021-9258

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