Cell death induced by granzyme C.
Although the functions of granzymes A and B have been defined, the functions of the other highly expressed granzymes (Gzms) of murine cytotoxic lymphocytes (C, D, and F) have not yet been evaluated. In this report, we describe the ability of murine GzmC (which is most closely related to human granzyme H) to cause cell death. The induction of death requires its protease activity and is characterized by the rapid externalization of phosphatidylserine, nuclear condensation and collapse, and single-stranded DNA nicking. The kinetics of these events are similar to those caused by granzyme B, and its potency (defined on a molar basis) is also equivalent. The induction of death did not involve the activation of caspases, the cleavage of BID, or the activation of the CAD nuclease. However, granzyme C did cause rapid mitochondrial swelling and depolarization in intact cells or in isolated mitochondria, and this mitochondrial damage was not prevented by cyclosporin A pretreatment. These results suggest that granzyme C rapidly induces target cell death by attacking nuclear and mitochondrial targets and that these targets are distinct from those used by granzyme B to cause classical apoptosis.
Johnson
Hillary
H
Division of Oncology, Department of Medicine, Siteman Cancer Center, Washington University School of Medicine, St Louis, MO 63110, USA.
Scorrano
Luca
L
Korsmeyer
Stanley J
SJ
Ley
Timothy J
TJ
D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D002467:Cell Nucleus / Q000187:drug effects; D016572:Cyclosporine / Q000494:pharmacology; D004249:DNA Damage; D053804:Granzymes; D006801:Humans; D007425:Intracellular Membranes / Q000187:drug effects; D008562:Membrane Glycoproteins / Q000494:pharmacology; D008563:Membrane Lipids / Q000032:analysis; D008564:Membrane Potentials / Q000187:drug effects; D051379:Mice; D008928:Mitochondria / Q000187:drug effects; D054353:Perforin; D010718:Phosphatidylserines / Q000032:analysis; D052899:Pore Forming Cytotoxic Proteins; D011993:Recombinant Fusion Proteins / Q000494:pharmacology; D012697:Serine Endopeptidases / Q000494:pharmacology*; D013379:Substrate Specificity; D014407:Tumor Cells, Cultured / Q000187:drug effects
D008562:Membrane Glycoproteins; D008563:Membrane Lipids; D010718:Phosphatidylserines; D052899:Pore Forming Cytotoxic Proteins; D011993:Recombinant Fusion Proteins; D054353:Perforin; D016572:Cyclosporine; C509213:GZMB protein, human; D053804:Granzymes; C509214:Gzmb protein, mouse; C509216:Gzmc protein, mouse; D012697:Serine Endopeptidases