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(Received for publication, July 10, 1996, and in revised form, August 26, 1996)
From the Lymphocyte granule-mediated apoptosis is
postulated to entail the formation of membrane pores by perforin. Then
soluble granzyme reaches the cytosol either through these pores or by
reparative pinocytosis. We demonstrate here that Jurkat cells bind and
internalize granzyme B via high affinity binding sites without toxic
consequence. Apoptosis occurs, however, if sublytic perforin is added
to targets washed free of soluble granzyme B. We suggest that
granule-mediated apoptosis mimics viral strategies for cellular entry.
Accordingly, co-internalization of granzyme B with adenovirus, a virus
that escapes endosomes to reach the cytosol, also induced apoptosis. Poly(ADP-ribose) polymerase cleavage and processing of CPP32, ICE-LAP3,
and Mch2 were detected at 30 min, while cytosolic acidification and DNA
fragmentation occurred at 60 min. Annexin V binding and membrane
permeabilization arose at 4 h. The concurrent activation of the
Ced-3 proteases differed from the rate at which each cysteine protease
is cleaved in vitro by granzyme B. Thus, granzyme B may not
directly process these proteases in whole cells but rather may function
by activating a more proximal enzyme. These results indicate that
adenovirus-mediated delivery of granzyme B is suitable for elucidating
biochemical events that accompany granule-mediated apoptosis.
Volume 271, Number 46,
Issue of November 15, 1996
pp. 29073-29079
©1996 by The American Society for Biochemistry and Molecular Biology, Inc.
TARGET CELLS BIND AND INTERNALIZE GRANZYME B, BUT AN
ENDOSOMOLYTIC AGENT IS NECESSARY FOR CYTOSOLIC DELIVERY AND
SUBSEQUENT APOPTOSIS
,
,
,
,
Department of Medicine, Evanston Hospital,
Northwestern University, Evanston, Illinois 60201, the
¶ Department of Pathology, University of Michigan Medical School,
Ann Arbor, Michigan 48109, the ** Medicine Branch, NCI, National
Institutes of Health, Bethesda, Maryland 20892, the
Division of Biochemistry, Scripps
Research Institute, San Diego, California 92037, the
§§ Poly(ADP-Ribose) Metabolism Group, Unit
of Health & Environment, Hospital and Research Center of Laval
University, Québec, Québec GIV 4G2, Canada, and the
¶¶ Department of Biochemistry, University of Alberta,
Edmonton, Alberta T6G 2H7, Canada
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