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
ISSN
0021-9258
Recommended Citation
Cilenti, Lucia; Soundarapandian, Mangala M.; Kyriazis, George A.; Stratico, Valerie; Singh, Supriya; Gupta, Sanjeev; Bonventre, Joseph V.; Alnemri, Emad S.; and Zervos, Antonis S., "Regulation of HAX-1 anti-apoptotic protein by Omi/HtrA2 protease during cell death" (2004). Faculty Bibliography 2000s. 4271.
https://stars.library.ucf.edu/facultybib2000/4271
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