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PMID:19026784

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Citation

Ditzel, M, Broemer, M, Tenev, T, Bolduc, C, Lee, TV, Rigbolt, KT, Elliott, R, Zvelebil, M, Blagoev, B, Bergmann, A and Meier, P (2008) Inactivation of effector caspases through nondegradative polyubiquitylation. Mol. Cell 32:540-53

Abstract

Ubiquitin-mediated inactivation of caspases has long been postulated to contribute to the regulation of apoptosis. However, detailed mechanisms and functional consequences of caspase ubiquitylation have not been demonstrated. Here we show that the Drosophila Inhibitor of Apoptosis 1, DIAP1, blocks effector caspases by targeting them for polyubiquitylation and nonproteasomal inactivation. We demonstrate that the conjugation of ubiquitin to drICE suppresses its catalytic potential in cleaving caspase substrates. Our data suggest that ubiquitin conjugation sterically interferes with substrate entry and reduces the caspase's proteolytic velocity. Disruption of drICE ubiquitylation, either by mutation of DIAP1's E3 activity or drICE's ubiquitin-acceptor lysines, abrogates DIAP1's ability to neutralize drICE and suppress apoptosis in vivo. We also show that DIAP1 rests in an "inactive" conformation that requires caspase-mediated cleavage to subsequently ubiquitylate caspases. Taken together, our findings demonstrate that effector caspases regulate their own inhibition through a negative feedback mechanism involving DIAP1 "activation" and nondegradative polyubiquitylation.

Links

PubMed PMC2713662 Online version:10.1016/j.molcel.2008.09.025

Keywords

Animals; Apoptosis/genetics; Apoptosis/physiology; Caspases/antagonists & inhibitors; Caspases/genetics; Caspases, Effector/antagonists & inhibitors; Caspases, Effector/genetics; Caspases, Effector/metabolism; Cells, Cultured; Drosophila/cytology; Drosophila/genetics; Drosophila/metabolism; Drosophila Proteins/antagonists & inhibitors; Drosophila Proteins/genetics; Drosophila Proteins/metabolism; Inhibitor of Apoptosis Proteins/genetics; Inhibitor of Apoptosis Proteins/metabolism; Kinetics; Models, Biological; Peptide Hydrolases/metabolism; Protein Conformation; Ubiquitin-Protein Ligases/chemistry; Ubiquitin-Protein Ligases/metabolism; Ubiquitination

Significance

Annotations

Gene product Qualifier GO Term Evidence Code with/from Aspect Extension Notes Status

DROME:DIAP1

involved_in

GO:0031398: positive regulation of protein ubiquitination

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

DROME:IAP1

involved_in

GO:0031398: positive regulation of protein ubiquitination

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete


See also

References

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