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Molecular and Cellular Biology, November 1998, p. 6387-6398, Vol. 18, No. 11
Department of Medicine,
Received 26 May 1998/Returned for modification 6 August
1998/Accepted 17 August 1998
Cytotoxic lymphocytes (CLs) induce caspase activation and apoptosis
of target cells either through Fas activation or through release of
granule cytotoxins, particularly granzyme B. CLs themselves resist
granule-mediated apoptosis but are eventually cleared via Fas-mediated
apoptosis. Here we show that the CL cytoplasmic serpin proteinase
inhibitor 9 (PI-9) can protect transfected cells against apoptosis
induced by either purified granzyme B and perforin or intact CLs. A
PI-9 P1 mutant (Glu to Asp) is a 100-fold-less-efficient granzyme B inhibitor that no longer protects against granzyme B-mediated apoptosis. PI-9 is highly specific for granzyme B because it
does not inhibit eight of the nine caspases tested or protect transfected cells against Fas-mediated apoptosis. In contrast, the
P1(Asp) mutant is an effective caspase inhibitor that
protects against Fas-mediated apoptosis. We propose that PI-9 shields
CLs specifically against misdirected granzyme B to prevent autolysis or
fratricide, but it does not interfere with homeostatic deletion via
Fas-mediated apoptosis.
0270-7306/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.
Selective Regulation of Apoptosis: the Cytotoxic Lymphocyte
Serpin Proteinase Inhibitor 9 Protects against Granzyme B-Mediated
Apoptosis without Perturbing the Fas Cell Death Pathway
*
Corresponding author. Mailing address: Department of
Medicine, Monash Medical School, Box Hill Hospital, Box Hill 3128, Australia. Phone: 61 3 9895 0316. Fax: 61 3 9895 0332. E-mail:
philb{at}boxhill.med.monash.edu.au.
Molecular and Cellular Biology, November 1998, p. 6387-6398, Vol. 18, No. 11
0270-7306/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.
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