Title

Regulation of HAX-1 anti-apoptotic protein by Omi/HtrA2 protease during cell death

Authors

Authors

L. Cilenti; M. M. Soundarapandian; G. A. Kyriazis; V. Stratico; S. Singh; S. Gupta; J. V. Bonventre; E. S. Alnemri;A. S. Zervos

Comments

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Abbreviated Journal Title

J. Biol. Chem.

Keywords

HEAT-SHOCK-PROTEIN; SERINE-PROTEASE; INHIBITOR; INTERACTS; HTRA; MITOCHONDRIA; CHAPERONE; DISEASE; ASSAY; MND2; Biochemistry & Molecular Biology

Abstract

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 antiapoptotic protein. This function is distinct from its ability to activate caspase-dependent apoptosis in the cytoplasm by degrading inhibitor of apoptosis proteins.

Journal Title

Journal of Biological Chemistry

Volume

279

Issue/Number

48

Publication Date

1-1-2004

Document Type

Article

Language

English

First Page

50295

Last Page

50301

WOS Identifier

WOS:000225229500092

ISSN

0021-9258

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