GRANULE-MEDIATED KILLING - PATHWAYS FOR GRANZYME B-INITIATED APOPTOSIS

We report that the serine protease granzyme B (GrB), which is crucial for granule-mediated cell killing, initiates apoptosis in target cells by first maturing caspase-10. In addition, GrB has a limited capacity to mature other caspases and to cause cell death independently of the caspases. Compared with other members, GrB in vitro most efficiently processes caspase-7 and -10. In a human cell model, full maturation of caspase-7 does not occur unless caspase-10 is present. Furthermore, G rB matured caspase-3 with less efficiency than caspase-7 or caspase-10 . With the caspases fully inactivated by peptidic inhibitors, GrB indu ced in Jurkat cells growth arrest and, over a delayed time period, cel l death. Thus, the primary mechanism by which GrB initiates cell death is activation of the caspases through caspase-10. However, under circ umstances where caspase-10 is absent or dysfunctional, GrB can act thr ough secondary mechanisms including activation of other caspases and d irect cell killing by cleavage of noncaspase substrates. The redundant functions of GrB ensure the effectiveness of granule-mediated cell ki lling, even in target cells that lack the expression or function (e.g. , by mutation or a viral serpin) of one or more of the caspases, provi ding the host with overlapping safeguards against aberrantly replicati ng, nonself or virally infected cells.