The PIDDosome, a protein complex implicated in activation of caspase-2 in response to genotoxic stress

Apoptosis is triggered by activation of initiator caspases upon complex-mediated clustering of the inactive zymogen, as occurs in the caspase-9-activating apoptosome complex. Likewise, caspase-2, which is involved in stress-induced Apoptosis, is recruited into a large protein complex, the molecular composition of which remains elusive. We show that activation of caspase-2 occurs in a complex that contains the death domain-containing protein PIDD, whose expression is induced by p53, and the adaptor protein RAIDD. Increased PIDD expression resulted in spontaneous activation of caspase-2 and sensitization to Apoptosis by genotoxic stimuli. Because PIDD functions in p53-mediated Apoptosis, the complex assembled by PIDD and caspase-2 is likely to regulate Apoptosis induced by genotoxins.