Granzyme M mediates a novel form of perforin-dependent cell death.
Cell death is mediated by cytotoxic lymphocytes through various granule serine proteases released with perforin. The unique protease activity, restricted expression, and distinct gene locus of granzyme M suggested this enzyme might have a novel biological function or trigger a novel form of cell death. Herein, we demonstrate that in the presence of perforin, the protease activity of granzyme M rapidly and effectively induces target cell death. In contrast to granzyme B, cell death induced by granzyme M does not feature obvious DNA fragmentation, occurs independently of caspases, caspase activation, and perturbation of mitochondria and is not inhibited by overexpression of Bcl-2. These data raise the likelihood that granzyme M represents a third major and specialized perforin-dependent cell death pathway that plays a significant role in death mediated by NK cells.
Kelly
Janice M
JM
Cancer Immunology Program, Peter MacCallum Cancer Centre, Locked Bag 1, A'Beckett St, 8006 Victoria, Australia.
Waterhouse
Nigel J
NJ
Cretney
Erika
E
Browne
Kylie A
KA
Ellis
Sarah
S
Trapani
Joseph A
JA
Smyth
Mark J
MJ
D000818:Animals; D017209:Apoptosis; D015153:Blotting, Western; D020169:Caspases / Q000378:metabolism; D016923:Cell Death; D002460:Cell Line; D002857:Chromium / Q000378:metabolism; D053938:DNA Fragmentation; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation; D004912:Erythrocytes / Q000378:metabolism; D053804:Granzymes; D006367:HeLa Cells; D006801:Humans; D007455:Iodine / Q000378:metabolism; D019169:Jurkat Cells; D020014:K562 Cells; D007694:Killer Cells, Natural / Q000378:metabolism; D008214:Lymphocytes / Q000378:metabolism; D008562:Membrane Glycoproteins / Q000378:metabolism; D008928:Mitochondria / Q000378:metabolism; D054353:Perforin; D052899:Pore Forming Cytotoxic Proteins; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D011994:Recombinant Proteins / Q000378:metabolism; D012697:Serine Endopeptidases / Q000378:metabolism / Q000502:physiology*; D012756:Sheep; D013997:Time Factors
D008562:Membrane Glycoproteins; D052899:Pore Forming Cytotoxic Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D011994:Recombinant Proteins; D002857:Chromium; D054353:Perforin; D007455:Iodine; C509213:GZMB protein, human; C509218:GZMM protein, human; D053804:Granzymes; D012697:Serine Endopeptidases; D020169:Caspases