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Published online December 31, 2007
doi:10.1083/jcb.200706027
The Journal of Cell Biology, Vol. 179, No. 7, 1467-1480
The Rockefeller University Press, 0021-9525 $30.00
© 2007 Ribeiro et al.
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Article

 DIAP2 functions as a mechanism-based regulator of drICE that contributes to the caspase activity threshold in living cells

Paulo S. Ribeiro1,2, Erina Kuranaga3, Tencho Tenev1, François Leulier1,4, Masayuki Miura3, and Pascal Meier1

1 Breakthrough Toby Robins Breast Cancer Research Centre, Institute of Cancer Research, London SW3 6JB, England, UK
2 Programa Gulbenkian de Doutoramento em Biomedicina, Instituto Gulbenkian de Ciência, Oeiras 2781-901, Portugal
3 Department of Genetics, Graduate School of Pharmaceutical Sciences, University of Tokyo, Bunkyo-ku, Tokyo 113-0033, Japan
4 Centre National de la Recherche Scientifique, Centre de Génétique Moléculaire, Gif-sur-Yvette 91190, France

Correspondence to P. Meier: Pascal.Meier{at}icr.ac.uk

In addition to their well-known function in apoptosis, caspases are also important in several nonapoptotic processes. How caspase activity is restrained and shut down under such nonapoptotic conditions remains unknown. Here, we show that Drosophila melanogaster inhibitor of apoptosis protein 2 (DIAP2) controls the level of caspase activity in living cells. Animals that lack DIAP2 have higher levels of drICE activity. Although diap2-deficient cells remain viable, they are sensitized to apoptosis following treatment with sublethal doses of x-ray irradiation. We find that DIAP2 regulates the effector caspase drICE through a mechanism that resembles the one of the caspase inhibitor p35. As for p35, cleavage of DIAP2 is required for caspase inhibition. Our data suggest that DIAP2 forms a covalent adduct with the catalytic machinery of drICE. In addition, DIAP2 also requires a functional RING finger domain to block cell death and target drICE for ubiquitylation. Because DIAP2 efficiently interacts with drICE, our data suggest that DIAP2 controls drICE in its apoptotic and nonapoptotic roles.

Abbreviations used in this paper: AO, acridine orange; BIR, baculovirus IAP repeat; DIAP2, Drosophila melanogaster IAP 2; FRET, fluorescence resonance energy transfer; Hid, head involution defective; IAP, inhibitor of apoptosis protein; IBM, IAP-binding motif; PARP, poly ADP ribose polymerase; Rpr, reaper; TAP, tandem affinity purification; WT, wild type; XIAP, x-linked IAP.


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