Granzyme B can cause mitochondrial depolarization and cell death in the absence of BID, BAX, and BAK.
Granzyme B (GzmB) is a serine protease that is used by activated cytotoxic T lymphocytes to induce target cell apoptosis. Although GzmB directly cleaves the Bcl2 family member BID on target cell entry, Bid-deficient (and Bax, Bak doubly deficient) cells are susceptible to GzmB-induced death, even though they fail to release cytochrome c from mitochondria. GzmB still induces mitochondrial depolarization in Bax, Bak double knockout cells without cytochrome c release or opening of the permeability transition pore. Because GzmB cannot directly cause depolarization of isolated mitochondria, novel intracellular factor(s) may be required for GzmB to depolarize mitochondria in situ. GzmB therefore utilizes two distinct mitochondrial pathways to amplify the proapoptotic signal that it delivers to target cells.
Thomas
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DA
Division of Oncology, Departments of Medicine and Genetics, Siteman Cancer Center, and Department of Molecular Biology and Pharmacology, Washington University School of Medicine, St. Louis, MO 63110, USA.
Scorrano
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L
Putcha
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GV
Korsmeyer
S J
SJ
Ley
T J
TJ
D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D051023:BH3 Interacting Domain Death Agonist Protein; D002352:Carrier Proteins / Q000502:physiology*; D002463:Cell Membrane Permeability; D003574:Cytochrome c Group / Q000378:metabolism; D005455:Fluorescent Antibody Technique; D053804:Granzymes; D008565:Membrane Proteins / Q000502:physiology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008930:Mitochondria, Liver / Q000187:drug effects* / Q000201:enzymology / Q000502:physiology; D011518:Proto-Oncogene Proteins / Q000502:physiology*; D019253:Proto-Oncogene Proteins c-bcl-2; D012697:Serine Endopeptidases / Q000494:pharmacology*; D013347:Subcellular Fractions / Q000378:metabolism; D050998:bcl-2 Homologous Antagonist-Killer Protein; D051028:bcl-2-Associated X Protein
D051023:BH3 Interacting Domain Death Agonist Protein; C494773:Bak1 protein, mouse; C494827:Bax protein, mouse; C494815:Bid protein, mouse; D002352:Carrier Proteins; D003574:Cytochrome c Group; D008565:Membrane Proteins; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D050998:bcl-2 Homologous Antagonist-Killer Protein; D051028:bcl-2-Associated X Protein; D053804:Granzymes; C509214:Gzmb protein, mouse; D012697:Serine Endopeptidases