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Genes & Dev. 17 (12): 1487-1496

Copyright © 2003 by Cold Spring Harbor Laboratory Press.

RESEARCH PAPER

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

Qi-Heng Yang1, Robin Church-Hajduk2, Jinyu Ren1, Michelle L. Newton1, and Chunying Du1,3

1 Stowers Institute for Medical Research, Kansas City, Missouri 64110, USA
2 Department of Anesthesiology, St. Luke's Hospital/UMKC, Kansas City, Missouri 64111, USA

Abstract: 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.

Key Words: Apoptosis • mitochondria • Omi/HtrA2 • Smac • IAPs • caspases

Received for publication March 27, 2003. Accepted for publication April 29, 2003.

Corresponding author.

3 E-MAIL cdu{at}Stowers-Institute.org; FAX (816) 926-2055.

Article and publication are at http://www.genesdev.org/cgi/doi/10.1101/gad.1097903.

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