Association of caspase-2 with the promyelocytic leukemia protein nuclear bodies.

Apoptotic cell death is executed by a family of cysteine proteases known as caspases. Synthesized as inactive precursors, caspases become activated sequentially in cascades. Activation of apical or initiator caspases in these cascades occurs in macromolecular complexes located in various compartments. One such complex is the plasma membrane-bound death-inducing signaling complex (DISC), formed upon engagement of death receptors, which recruits and activates caspase-8 and -10. Another complex is the cytosolic apoptosome, assembled in response to the release of mitochondrial cytochrome c, which recruits caspase-9. The other major human initiator caspase is caspase-2, which is activated in response to various lethal stimuli and has recently been shown to be required for DNA damage-induced apoptosis. The regulation of caspase-2 is not well understood. Here we present evidence that caspase-2 is localized to the promyelocytic leukemia protein nuclear bodies (PML-NBs), nuclear macro-molecular complexes that are involved in many scenarios of apoptosis including DNA damage. The localization of caspase-2 requires both the prodomain and protease domain but appears to be independent of its adaptor protein, CRADD/RAIDD. These data suggest the existence of a nuclear apoptosis pathway that involves both caspase-2 and the PML-NBs.