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IAPs are functionally non-equivalent and regulate effector caspases through distinct mechanisms

Nature Cell Biology volume 7, pages 70–77 (2005)Cite this article

Abstract

Some members of the inhibitor of apoptosis (IAP) family suppress apoptosis by neutralizing caspases. The current model suggests that all caspase-regulatory IAPs function as direct enzyme inhibitors, blocking effector caspases by binding to their catalytically active pockets. Here we show that IAPs are functionally non-equivalent and regulate effector caspases through distinct mechanisms. Whereas XIAP binds directly to the active-site pockets of effector caspases, we find that regulation of effector caspases by Drosophila IAP1 (DIAP1) requires an evolutionarily conserved IAP-binding motif (IBM) at the neo-amino terminus of the large caspase subunit. Remarkably, unlike XIAP, DIAP1-sequestered effector caspases remain catalytically active, suggesting that DIAP1 does not function as a bona fide enzyme inhibitor. Moreover, we demonstrate that the mammalian IAP c-IAP1 interacts with caspase-7 in an exclusively IBM-dependent, but active site pocket-independent, manner that is mechanistically similar to DIAP1. The importance of IBM-mediated regulation of effector-caspases in vivo is substantiated by the enhanced apoptotic potency of IBM-mutant versions of drICE, DCP-1 and caspase-7.

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Figure 1: The BIR1 domain plus the adjacent linker region are essential for binding of DIAP1 to effector caspases.
Figure 2: The IBM of drICE and DCP-1 is indispensable for binding to DIAP1.
Figure 3: DIAP1-bound caspases remain catalytically active.
Figure 4: IBM-dependent regulation of caspases.
Figure 5: The IBM of caspase-7 is indispensable for its interaction with c-IAP1.

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Acknowledgements

We thank A. Varshavsky and F. Levy for the ubiquitin fusion construct and B. Seraphin for the TAP construct. We thank F. Leulier, S. Schneider, A. Ashworth and J. Silke for critical reading of the manuscript.

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  1. The Breakthrough Toby Robins Breast Cancer Research Centre, Institute of Cancer Research, Mary-Jean Mitchell Green Building, Chester Beatty Laboratories, Fulham Road, London, SW3 6JB, UK

    Tencho Tenev, Anna Zachariou, Rebecca Wilson, Mark Ditzel & Pascal Meier

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  1. Tencho Tenev
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  2. Anna Zachariou
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Correspondence to Pascal Meier.

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Tenev, T., Zachariou, A., Wilson, R. et al. IAPs are functionally non-equivalent and regulate effector caspases through distinct mechanisms. Nat Cell Biol 7, 70–77 (2005). https://doi.org/10.1038/ncb1204

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