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Published online
doi:10.1083/jcb.200811105
The Journal of Cell Biology, Vol. 185, No. 2, 291-303
The Rockefeller University Press, 0021-9525 $30.00
© Manzl et al.
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Article

Caspase-2 activation in the absence of PIDDosome formation



Claudia Manzl1, Gerhard Krumschnabel1, Florian Bock1, Benedicte Sohm1, Verena Labi1, Florian Baumgartner1, Emmanuelle Logette2, Jürg Tschopp2, and Andreas Villunger1

1 Division of Developmental Immunology, Biocenter, Innsbruck Medical University, A-6020 Innsbruck, Austria
2 Department of Biochemistry, University of Lausanne, CH-1066 Epalinges, Switzerland

Correspondence to Andreas Villunger: Andreas.Villunger{at}i-med.ac.at

PIDD (p53-induced protein with a death domain [DD]), together with the bipartite adapter protein RAIDD (receptor-interacting protein-associated ICH-1/CED-3 homologous protein with a DD), is implicated in the activation of pro–caspase-2 in a high molecular weight complex called the PIDDosome during apoptosis induction after DNA damage. To investigate the role of PIDD in cell death initiation, we generated PIDD-deficient mice. Processing of caspase-2 is readily detected in the absence of PIDDosome formation in primary lymphocytes. Although caspase-2 processing is delayed in simian virus 40–immortalized pidd–/– mouse embryonic fibroblasts, it still depends on loss of mitochondrial integrity and effector caspase activation. Consistently, apoptosis occurs normally in all cell types analyzed, suggesting alternative biological roles for caspase-2 after DNA damage. Because loss of either PIDD or its adapter molecule RAIDD did not affect subcellular localization, nuclear translocation, or caspase-2 activation in high molecular weight complexes, we suggest that at least one alternative PIDDosome-independent mechanism of caspase-2 activation exists in mammals in response to DNA damage.

Abbreviations used in this paper: DD, death domain; GAPDH, glyceraldehyde-3-phosphate dehydrogenase; MEF, mouse embryonic fibroblast; MOMP, mitochondrial outer membrane permeabilization; mPIDD, mouse PIDD; NF-{kappa}B, nuclear factor {kappa}B; PE, phycoerythrin; PI, propidium iodide; Puma, p53 up-regulated modulator of apoptosis; UVR, UV radiation.

© 2009 Manzl et al.
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