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(Received for publication, March 6, 1996, and in revised form, May 16, 1996)
,
and
From the Cytotoxic T lymphocytes (CTLs) are able to
recognize and destroy target cells bearing foreign antigen using one of
two distinct mechanisms: granule- or Fas-mediated cytotoxicity. The
exact mechanisms involved in the induction of apoptotic cell death
remain elusive; however, it seems likely that a family of cysteine
proteases related to interleukin-1
Department of Biochemistry, University of
Alberta, Edmonton, Alberta T6G 2H7, Canada, the ¶ Departments of
Genetics and Medicine, Division of Bone Marrow Transplantation and Stem
Cell Biology, Washington University Medical School, St. Louis, Missouri
63110, and the 
Department of Biochemistry and Molecular Biology,
Merck Frosst Centre for Therapeutic Research, Pointe Claire Dorval,
Quebec H9R 4P8, Canada
converting enzyme are involved.
One family member, CPP32, has been identified as an intracellular
substrate for granzyme B, a CTL-specific serine protease responsible
for the early induction of target cell DNA fragmentation. Here we use
cytolytic cells from granzyme B-deficient mice to confirm that cleavage
and activation of CPP32 represents a nonredundant role for granzyme B
and that this activation plays a role in the induction of DNA
fragmentation in target cells, a signature event for apoptotic cell
death. A peptide inhibitor of CPP32-like proteases confirmed the
function of these enzymes in fragmentation. 51Cr release
was not suppressed under these conditions, suggesting that granzyme B
cleavage of CPP32 is primarily involved in the induction of DNA
fragmentation and not membrane damage during CTL-induced apoptosis.
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