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https://hdl.handle.net/2440/9061
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Type: | Journal article |
Title: | Selective regulation of apoptosis: the cytoxic lymphocyte serpin, proteinase inhibitor 9 protects against granzyme B-mediated apoptosis without perturbing the FAS Cell death pathway |
Author: | Bird, C. Sutton, V. Sun, J. Hirst, C. Novak, A. Kumar, S. Trapani, J. Bird, P. |
Citation: | Molecular and Cellular Biology, 1998; 18(11):6387-6398 |
Publisher: | AMER SOC MICROBIOLOGY |
Issue Date: | 1998 |
ISSN: | 0270-7306 1098-5549 |
Statement of Responsibility: | Catherina H. Bird, Vivien R. Sutton, Jiuru Sun, Claire E. Hirst, Andrea Novak, Sharad Kumar, Joseph A. Trapani, and Phillip I. Bird |
Abstract: | 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. |
Keywords: | T-Lymphocytes, Cytotoxic Tumor Cells, Cultured Humans Recombinant Proteins Serpins Microscopy, Fluorescence Flow Cytometry Transfection Apoptosis Amino Acid Sequence Molecular Sequence Data Caspase Inhibitors fas Receptor |
DOI: | 10.1128/MCB.18.11.6387 |
Published version: | http://dx.doi.org/10.1128/mcb.18.11.6387 |
Appears in Collections: | Aurora harvest 4 Medicine publications |
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