GRANZYME-B DIRECTLY AND EFFICIENTLY CLEAVES SEVERAL DOWNSTREAM CASPASE SUBSTRATES - IMPLICATIONS FOR CTL-INDUCED APOPTOSIS

Caspase-mediated proteolysis of downstream substrates is a critical el ement of the execution pathway common to all forms of apoptosis studie d to date. While this caspase-dependent pathway is activated during cy totoxic lymphocyte granule-induced cell death, recent studies have als o provided evidence for caspase-independent pathways. However, the mec hanisms mediating these additional pathways have not been defined. The current study demonstrates that DNA-PKcs, and NuMA are directly and e fficiently cleaved by granzyme B in vitro and in vivo, generating uniq ue substrate fragments not observed during other forms of apoptosis. T his direct, caspase-independent ability of granzyme B to cleave downst ream death substrates constitutes an apoptotic effector mechanism that is insensitive to inhibitors of the signaling or execution components of the endogenous apoptotic cascade.