Caspase-2 activation in the absence of PIDDosome formation.
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.
Division of Developmental Immunology, Biocenter, Innsbruck Medical University, A-6020 Innsbruck, Austria.
Claudia
C
Manzl
Gerhard
G
Krumschnabel
Florian
F
Bock
Benedicte
B
Sohm
Verena
V
Labi
Florian
F
Baumgartner
Emmanuelle
E
Logette
Jürg
J
Tschopp
Andreas
A
Villunger
D000818:Animals; D017209:Apoptosis / Q000502:physiology; D053420:CRADD Signaling Adaptor Protein / Q000235:genetics / Q000378:metabolism; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D053143:Caspase 2 / Q000235:genetics / Q000378:metabolism*; D002478:Cells, Cultured; D045304:Cytochromes c / Q000378:metabolism; D004249:DNA Damage; D053418:Death Domain Receptor Signaling Adaptor Proteins; D004789:Enzyme Activation; D005260:Female; D005347:Fibroblasts / Q000166:cytology / Q000502:physiology; D005720:Gamma Rays; D006801:Humans; D008214:Lymphocytes / Q000166:cytology / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008928:Mitochondria / Q000378:metabolism; D046912:Multiprotein Complexes / Q000737:chemistry / Q000378:metabolism*; D011498:Protein Precursors / Q000235:genetics / Q000378:metabolism
D053420:CRADD Signaling Adaptor Protein; D002352:Carrier Proteins; C484481:Cradd protein, mouse; D053418:Death Domain Receptor Signaling Adaptor Proteins; D046912:Multiprotein Complexes; C414729:Pidd1 protein, mouse; D011498:Protein Precursors; D045304:Cytochromes c; D053143:Caspase 2