Granzyme A Induces Caspase-Independent Mitochondrial Damage, a Required First Step for Apoptosis

Granzyme A (GzmA) triggers cell death with apoptotic features by targeting the endoplasmic reticulum-associated SET complex, which contains the GzmA-activated DNase NM23-H1, its inhibitor SET, and Ape1. The SET complex was postulated to translocate to the nucleus in response to oxidative stress and...

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Bibliographic Details
Published in:Immunity (Cambridge, Mass.) Mass.), 2005-03, Vol.22 (3), p.355-370
Main Authors: Martinvalet, Denis, Zhu, Pengcheng, Lieberman, Judy
Format: Article
Language:English
Subjects:
Animals
Apoptosis
Apoptosis - drug effects
Caspases - immunology
Cells, Cultured
Cytotoxicity Tests, Immunologic
Cytotoxicity, Immunologic
Deoxyribonucleic acid
DNA
Enzymes
Granzymes
Humans
Jurkat Cells
Membrane Potentials - drug effects
Microscopy
Microscopy, Confocal
Mitochondria - drug effects
Mitochondria - pathology
Proteins
Reactive Oxygen Species - immunology
Serine Endopeptidases - immunology
Serine Endopeptidases - pharmacology
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Summary:Granzyme A (GzmA) triggers cell death with apoptotic features by targeting the endoplasmic reticulum-associated SET complex, which contains the GzmA-activated DNase NM23-H1, its inhibitor SET, and Ape1. The SET complex was postulated to translocate to the nucleus in response to oxidative stress and participate in its repair. Because mitochondrial damage is important in apoptosis, we investigated whether GzmA damages mitochondria. GzmA induces a rapid increase in reactive oxygen species and mitochondrial transmembrane potential loss, but does not cleave bid or cause apoptogenic factor release. The mitochondrial effect is direct, does not require cytosol, and is insensitive to bcl-2 and caspase inhibition. SET complex nuclear translocation, which occurs within minutes of peroxide or GzmA treatment, is dependent on superoxide generation since superoxide scavengers block it. Superoxide scavengers also block apoptosis by CTLs expressing GzmA and/or GzmB. Therefore, mitochondrial damage is an essential first step in killer cell granule-mediated pathways of apoptosis.
ISSN:1074-7613
1097-4180
DOI:10.1016/j.immuni.2005.02.004