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PMID: 12815069 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't

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

Genes & development ·Vol. 17 ·No. 12 ·2003-06-15 ·Pages 1487-96

Yang QH, Church-Hajduk R, Ren J, Newton ML, Du C

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.

MeSH Terms
Apoptosis/physiology Apoptosis Regulatory Proteins Binding Sites Carrier Proteins/metabolism Caspases/metabolism Catalysis Enzyme Activation/physiology HeLa Cells High-Temperature Requirement A Serine Peptidase 2 Humans Inhibitor of Apoptosis Proteins Intracellular Signaling Peptides and Proteins Ligases/metabolism Membrane Glycoproteins/metabolism Mitochondrial Proteins/metabolism Mutation Protein Structure, Tertiary Proteins/genetics,metabolism Serine Endopeptidases/genetics,metabolism Substrate Specificity TNF-Related Apoptosis-Inducing Ligand Tumor Necrosis Factor-alpha/metabolism Ubiquitin/metabolism Ubiquitin-Protein Ligases
Chemicals
Apoptosis Regulatory Proteins Carrier Proteins DIABLO protein, human Inhibitor of Apoptosis Proteins Intracellular Signaling Peptides and Proteins Membrane Glycoproteins Mitochondrial Proteins Proteins TNF-Related Apoptosis-Inducing Ligand TNFSF10 protein, human Tumor Necrosis Factor-alpha Ubiquitin BIRC2 protein, human Ubiquitin-Protein Ligases Serine Endopeptidases HTRA2 protein, human High-Temperature Requirement A Serine Peptidase 2 Caspases Ligases
Authors & Affiliations
5 authors, click to expand affiliations / ORCID
Yang Qi-Heng
Stowers Institute for Medical Research, Kansas City, MO 64110, USA.
Church-Hajduk Robin
Ren Jinyu
Newton Michelle L
Du Chunying
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Article Info
Journal
Genes & development
Abbr.
Genes Dev
ISSN
0890-9369
DOI
10.1101/gad.1097903
Published
2003-06-15
Pages
1487-96
Language
English
Region
United States
NLM ID
8711660
PMCID
PMC196079
Subset
IM
External Links
PubMed source DOI: 10.1101/gad.1097903 PMC Full Text View journal details
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