Omi/HtrA2 catalytic cleavage of inhibitor of apoptosis (IAP) irreversibly inactivates IAPs and facilitates caspase activity in apoptosis.

Omi/HtrA2 is a mitochondrial serine protease that is released into the cytosol during apoptosis to antagonize inhibitors of apoptosis (IAPs) and contribute to caspase-independent cell death. Here, we demonstrate that Omi/HtrA2 directly cleaves various IAPs in vitro, and the cleavage efficiency is determined by its IAP-binding motif, AVPS. Cleavage of ...
IAPs such as c-IAP1 substantially reduces its ability to inhibit and ubiquitylate caspases. In contrast to the stoichiometric anti-IAP activity by Smac/DIABLO, Omi/HtrA2 cleavage of c-IAP1 is catalytic and irreversible, thereby more efficiently inactivating IAPs and promoting caspase activity. Elimination of endogenous Omi by RNA interference abolishes c-IAP1 cleavage and desensitizes cells to apoptosis induced by TRAIL. In addition, overexpression of cleavage-site mutant c-IAP1 makes cells more resistant to TRAIL-induced caspase activation. This IAP cleavage by Omi is independent of caspase. Taken together, these results indicate that unlike Smac/DIABLO, Omi/HtrA2's catalytic cleavage of IAPs is a key mechanism for it to irreversibly inactivate IAPs and promote apoptosis.
Mesh Terms:
Apoptosis, Apoptosis Regulatory Proteins, Binding Sites, Carrier Proteins, Caspases, Catalysis, Enzyme Activation, Hela Cells, Humans, Inhibitor of Apoptosis Proteins, Intracellular Signaling Peptides and Proteins, Ligases, Membrane Glycoproteins, Mitochondrial Proteins, Mutation, Protein Structure, Tertiary, Proteins, Serine Endopeptidases, Substrate Specificity, TNF-Related Apoptosis-Inducing Ligand, Tumor Necrosis Factor-alpha, Ubiquitin
Genes Dev.
Date: Jun. 15, 2003
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