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Inhibitor of apoptosis (IAP) proteins inhibit caspases, a function counteracted by IAP antagonists, insect Grim, HID, and Reaper and mammalian DIABLO/Smac. We now demonstrate that HtrA2, a mammalian homologue of the Escherichia coli heat shock-inducible protein HtrA, can bind to MIHA/XIAP, MIHB, and baculoviral OpIAP but not survivin. Although produced as a 50-kDa protein, HtrA2 is processed to yield an active serine protease with an N terminus similar to that of Grim, Reaper, HID, and DIABLO/Smac that mediates its interaction with XIAP. HtrA2 is largely membrane-associated in healthy cells, with a significant proportion observed within the mitochondria, but in response to UV irradiation, HtrA2 shifts into the cytosol, where it can interact with IAPs. HtrA2 can, like DIABLO/Smac, prevent XIAP inhibition of active caspase 3 in vitro and is able to counteract XIAP protection of mammalian NT2 cells against UV-induced cell death. The proapoptotic activity of HtrA2 in vivo involves both IAP binding and serine protease activity. Mutations of either the N-terminal alanine of mature HtrA2 essential for IAP interaction or the catalytic serine residue reduces the ability of HtrA2 to promote cell death, whereas a complete loss in proapoptotic activity is observed when both sites are mutated.

Original publication

DOI

10.1074/jbc.M109891200

Type

Journal article

Journal

J Biol Chem

Publication Date

04/01/2002

Volume

277

Pages

445 - 454

Keywords

Amino Acid Sequence, Apoptosis, Binding Sites, Caspase 3, Caspase Inhibitors, Chromosomal Proteins, Non-Histone, Cytosol, High-Temperature Requirement A Serine Peptidase 2, Humans, Inhibitor of Apoptosis Proteins, Microtubule-Associated Proteins, Mitochondria, Mitochondrial Proteins, Molecular Sequence Data, Neoplasm Proteins, Proteins, Serine Endopeptidases, Ultraviolet Rays, X-Linked Inhibitor of Apoptosis Protein