DIAP2 functions as a mechanism-based regulator of drICE that contributes to the caspase activity threshold in living cells.
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.
Ribeiro
Paulo S
PS
Breakthrough Toby Robins Breast Cancer Research Centre, Institute of Cancer Research, London SW3 6JB, England, UK.
Kuranaga
Erina
E
Tenev
Tencho
T
Leulier
François
F
Miura
Masayuki
M
Meier
Pascal
P
D000818:Animals; D017209:Apoptosis / Q000502:physiology* / Q000528:radiation effects; D020169:Caspases / Q000378:metabolism*; D020134:Catalytic Domain / Q000502:physiology; D002470:Cell Survival / Q000502:physiology / Q000528:radiation effects; D029721:Drosophila Proteins / Q000378:metabolism*; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins / Q000378:metabolism*; D051379:Mice; D041681:NIH 3T3 Cells; D011485:Protein Binding / Q000502:physiology; D054829:RING Finger Domains / Q000502:physiology; D054875:Ubiquitination / Q000502:physiology; D014965:X-Rays
C111892:DIAP2 protein, Drosophila; D029721:Drosophila Proteins; D051034:Inhibitor of Apoptosis Proteins; D020169:Caspases; C109171:drICE protein, Drosophila