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A Triple-Mutated Allele of Granzyme B Incapable of Inducing Apoptosis
Dorian McIlroy, Pierre-François Cartron, Pierre Tuffery, Yasmine Dudoit, Assia Samri, Brigitte Autran, François M. Vallette, Patrice Debré and Ioannis Theodorou
Proceedings of the National Academy of Sciences of the United States of America
Vol. 100, No. 5 (Mar. 4, 2003), pp. 2562-2567
Published by: National Academy of Sciences
Stable URL: http://www.jstor.org/stable/3139567
Page Count: 6
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Granzyme B (GzmB) is a serine protease involved in many pathologies, including viral infections, autoimmunity, transplant rejection, and antitumor immunity. To measure the extent of genetic variation in GzmB, we screened the GzmB gene for polymorphisms and defined a frequently represented triple-mutated GzmB allele. In this variant, three amino acids of the mature protein Q48P88Y245 are mutated to R48A88H245. In CD8+ cytotoxic T lymphocytes, GzmB was expressed at similar levels in QPY homozygous, QPY/RAH heterozygous, and RAH homozygous individuals, demonstrating that RAH GzmB is a stable protein. Active RAH GzmB expressed in glioblastoma cell lines displayed proteolytic activity, but in contrast to QPY GzmB, it did not accumulate in the nucleus and was unable to induce Bid cleavage, cytochrome c release, or apoptosis. Molecular modeling showed that the three amino acid substitutions clustered near the C-terminal α-helix of the protein, indicating that this region of the protein may be involved in the intracellular targeting of GzmB. The triple-mutated GzmB allele that we describe appears to be incapable of inducing apoptosis in tumor cell lines, and its presence could, therefore, influence both the prognosis of cancer patients and the success rates of antitumor cellular immunotherapy.
Proceedings of the National Academy of Sciences of the United States of America © 2003 National Academy of Sciences