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Omi/HtrA2 catalytic cleavage of inhibitor of apoptosis (IAP) irreversibly inactivates IAPs and facilitates caspase activity in apoptosis
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| Zeitschriftentitel: | Genes & Development |
|---|---|
| Personen und Körperschaften: | , , , , |
| In: | Genes & Development, 17, 2003, 12, S. 1487-1496 |
| Format: | E-Article |
| Sprache: | Englisch |
| veröffentlicht: |
Cold Spring Harbor Laboratory
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| Schlagwörter: |
| author_facet |
Yang, Qi-Heng Church-Hajduk, Robin Ren, Jinyu Newton, Michelle L. Du, Chunying Yang, Qi-Heng Church-Hajduk, Robin Ren, Jinyu Newton, Michelle L. Du, Chunying |
|---|---|
| author |
Yang, Qi-Heng Church-Hajduk, Robin Ren, Jinyu Newton, Michelle L. Du, Chunying |
| spellingShingle |
Yang, Qi-Heng Church-Hajduk, Robin Ren, Jinyu Newton, Michelle L. Du, Chunying Genes & Development Omi/HtrA2 catalytic cleavage of inhibitor of apoptosis (IAP) irreversibly inactivates IAPs and facilitates caspase activity in apoptosis Developmental Biology Genetics |
| author_sort |
yang, qi-heng |
| spelling |
Yang, Qi-Heng Church-Hajduk, Robin Ren, Jinyu Newton, Michelle L. Du, Chunying 0890-9369 1549-5477 Cold Spring Harbor Laboratory Developmental Biology Genetics http://dx.doi.org/10.1101/gad.1097903 <jats:p>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.</jats:p> Omi/HtrA2 catalytic cleavage of inhibitor of apoptosis (IAP) irreversibly inactivates IAPs and facilitates caspase activity in apoptosis Genes & Development |
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10.1101/gad.1097903 |
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Cold Spring Harbor Laboratory, 2003 |
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Cold Spring Harbor Laboratory, 2003 |
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| title |
Omi/HtrA2 catalytic cleavage of inhibitor of apoptosis (IAP) irreversibly inactivates IAPs and facilitates caspase activity in apoptosis |
| title_unstemmed |
Omi/HtrA2 catalytic cleavage of inhibitor of apoptosis (IAP) irreversibly inactivates IAPs and facilitates caspase activity in apoptosis |
| title_full |
Omi/HtrA2 catalytic cleavage of inhibitor of apoptosis (IAP) irreversibly inactivates IAPs and facilitates caspase activity in apoptosis |
| title_fullStr |
Omi/HtrA2 catalytic cleavage of inhibitor of apoptosis (IAP) irreversibly inactivates IAPs and facilitates caspase activity in apoptosis |
| title_full_unstemmed |
Omi/HtrA2 catalytic cleavage of inhibitor of apoptosis (IAP) irreversibly inactivates IAPs and facilitates caspase activity in apoptosis |
| title_short |
Omi/HtrA2 catalytic cleavage of inhibitor of apoptosis (IAP) irreversibly inactivates IAPs and facilitates caspase activity in apoptosis |
| title_sort |
omi/htra2 catalytic cleavage of inhibitor of apoptosis (iap) irreversibly inactivates iaps and facilitates caspase activity in apoptosis |
| topic |
Developmental Biology Genetics |
| url |
http://dx.doi.org/10.1101/gad.1097903 |
| publishDate |
2003 |
| physical |
1487-1496 |
| description |
<jats:p>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.</jats:p> |
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| author | Yang, Qi-Heng, Church-Hajduk, Robin, Ren, Jinyu, Newton, Michelle L., Du, Chunying |
| author_facet | Yang, Qi-Heng, Church-Hajduk, Robin, Ren, Jinyu, Newton, Michelle L., Du, Chunying, Yang, Qi-Heng, Church-Hajduk, Robin, Ren, Jinyu, Newton, Michelle L., Du, Chunying |
| author_sort | yang, qi-heng |
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| description | <jats:p>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.</jats:p> |
| doi_str_mv | 10.1101/gad.1097903 |
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| imprint | Cold Spring Harbor Laboratory, 2003 |
| imprint_str_mv | Cold Spring Harbor Laboratory, 2003 |
| institution | DE-15, DE-Pl11, DE-Rs1, DE-105, DE-14, DE-Ch1, DE-L229, DE-D275, DE-Bn3, DE-Brt1, DE-D161, DE-Zwi2, DE-Gla1, DE-Zi4 |
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| physical | 1487-1496 |
| publishDate | 2003 |
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| series | Genes & Development |
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| spelling | Yang, Qi-Heng Church-Hajduk, Robin Ren, Jinyu Newton, Michelle L. Du, Chunying 0890-9369 1549-5477 Cold Spring Harbor Laboratory Developmental Biology Genetics http://dx.doi.org/10.1101/gad.1097903 <jats:p>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.</jats:p> Omi/HtrA2 catalytic cleavage of inhibitor of apoptosis (IAP) irreversibly inactivates IAPs and facilitates caspase activity in apoptosis Genes & Development |
| spellingShingle | Yang, Qi-Heng, Church-Hajduk, Robin, Ren, Jinyu, Newton, Michelle L., Du, Chunying, Genes & Development, Omi/HtrA2 catalytic cleavage of inhibitor of apoptosis (IAP) irreversibly inactivates IAPs and facilitates caspase activity in apoptosis, Developmental Biology, Genetics |
| title | Omi/HtrA2 catalytic cleavage of inhibitor of apoptosis (IAP) irreversibly inactivates IAPs and facilitates caspase activity in apoptosis |
| title_full | Omi/HtrA2 catalytic cleavage of inhibitor of apoptosis (IAP) irreversibly inactivates IAPs and facilitates caspase activity in apoptosis |
| title_fullStr | Omi/HtrA2 catalytic cleavage of inhibitor of apoptosis (IAP) irreversibly inactivates IAPs and facilitates caspase activity in apoptosis |
| title_full_unstemmed | Omi/HtrA2 catalytic cleavage of inhibitor of apoptosis (IAP) irreversibly inactivates IAPs and facilitates caspase activity in apoptosis |
| title_short | Omi/HtrA2 catalytic cleavage of inhibitor of apoptosis (IAP) irreversibly inactivates IAPs and facilitates caspase activity in apoptosis |
| title_sort | omi/htra2 catalytic cleavage of inhibitor of apoptosis (iap) irreversibly inactivates iaps and facilitates caspase activity in apoptosis |
| title_unstemmed | Omi/HtrA2 catalytic cleavage of inhibitor of apoptosis (IAP) irreversibly inactivates IAPs and facilitates caspase activity in apoptosis |
| topic | Developmental Biology, Genetics |
| url | http://dx.doi.org/10.1101/gad.1097903 |