Author:
Zhang Dong,Beresford Paul J.,Greenberg Arnold H.,Lieberman Judy
Abstract
Cytotoxic T lymphocytes (CTL) induce apoptosis by engaging
death receptors or by exocytosis of cytolytic granules containing
granzyme (Gzm) proteases and perforin. The lamins, which maintain the
structural integrity of the nuclear envelope, are cleaved by caspases
during caspase-mediated apoptosis. Although death receptor
engagement and GzmB activate caspases, CTL also induce
apoptosis during caspase blockade. Both GzmA and GzmB directly
and efficiently cleave laminB in vitro, in
situ in isolated nuclei and in cells loaded with perforin and
Gzms, even in the presence of caspase inhibitors. LaminB is cleaved by
GzmA at concentrations of 3 nM, but GzmB is 50 times less active. GzmA
cuts laminB at R392; GzmB cuts at the caspase VEVD231 site.
Characteristic laminB fragments generated by Gzm proteolysis also are
observed during CTL lysis, even in the presence of caspase inhibitors
or in cells overexpressing bcl-2. Lamins A/C are direct substrates of
GzmA, but not GzmB. GzmA and GzmB therefore directly target critical
caspase substrates in caspase-resistant cells.
Publisher
Proceedings of the National Academy of Sciences
Cited by
138 articles.
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