The Journal of Experimental Medicine
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© The Rockefeller University Press, 0022-1007/1997/10/1323/ $5.00
The Journal of Experimental Medicine, Volume 186, Number 8, October 20, 1997 1323-1331

Articles

Granule-mediated Killing: Pathways for Granzyme B–initiated Apoptosis

Robert V. Talanian*, XiaoHe Yang{ddagger}, Jane Turbov{ddagger}, Prem Seth, Tariq Ghayur*, Carlos A. Casiano§, Kim Orth||, and Christopher J. Froelich{ddagger}

From the * BASF Bioresearch Corporation, Worcester, Massachusetts 01605; {ddagger} 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

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.

Address correspondence to Dr. Christopher J. Froelich, Evanston Hospital, Research Department, WH Building, Rm B624, 2650 Ridge Ave., Evanston, IL 60201. Phone: 847-570-2348; FAX: 847-570-1253; E-mail: granzyme{at}merle.acns.nwu.edu

1 Abbreviations used in this paper: AD, replication-deficient adenovirus type 2; GrB, granzyme B; PFN, perforin; PARP, poly-(ADP-ribose) polymerase; PI, propidium iodide; FITC–TUNEL, terminal deoxyribonucleotidyl transferase labeling of DNA strand breaks with FITC–dUTP; snRNP, small nuclear ribonucleoprotein.


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