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From the * BASF Bioresearch Corporation, Worcester, Massachusetts 01605; 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, GrB matured caspase-3 with less efficiency than caspase-7 or caspase-10. With
the caspases fully inactivated by peptidic inhibitors, GrB induced in Jurkat cells growth arrest
and, over a delayed time period, cell death. Thus, the primary mechanism by which GrB initiates cell death is activation of the caspases through caspase-10. However, under circumstances
where caspase-10 is absent or dysfunctional, GrB can act through secondary mechanisms including activation of other caspases and direct cell killing by cleavage of noncaspase substrates. The redundant functions of GrB ensure the effectiveness of granule-mediated cell killing, 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, providing the host with overlapping safeguards against aberrantly replicating, nonself or virally infected cells.
Department of Medicine,
Evanston Hospital, Northwestern University, Evanston, Illinois 60201; § W.M. Keck Autoimmune
Disease Center, Scripps Research Institute, La Jolla, California 92037; Biological Chemistry,
University of Michigan Medical School, Ann Arbor, Michigan 48109; and the ¶ Medicine Branch,
National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892
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