Granzyme B leakage-induced cell death: a new type of activation-induced natural killer cell death.
Activation-induced natural killer (NK) cell death is very rapid compared to activation-induced T or B cell death. Here we show that NK cell activation is accompanied by the leakage of granzymeB from intracellular granules into the cytoplasm. Evidence for granzyme B leakage includes the formation of granzyme B/serine proteinase inhibitor 9 (PI-9) complexes that are detected by immunoprecipitation as well as colocalization of granzyme B and PI-9 detected by immunocytochemistry. The pro-apoptotic molecule Bid, a specific substrate for granzyme B, was cleaved within 2 min following CD2-induced NK cell activation, suggesting that granzyme B triggers apoptosis by directing Bid to mitochondrial membranes. The granzyme B/PI-9 protein ratio was found to mirror the percentage of CD2-induced NK cell death, suggesting that an excess of leaked granzyme B over its inhibitor is a major determinant of cell death. We suggest that granzyme B leakage-induced cell death is an important determinant of activation-induced NK cell death and that this process may be important for the fate of NK cells which encounter malignant or virus-infected cells.
Ida
Hiroaki
H
First Department of Internal Medicine, Nagasaki University School of Medicine, Nagasaki, Japan. idah@net.nagasaki-u.ac.jp
Nakashima
Tomoki
T
Kedersha
Nancy L
NL
Yamasaki
Satoshi
S
Huang
Mingguo
M
Izumi
Yasumori
Y
Miyashita
Taiichiro
T
Origuchi
Tomoki
T
Kawakami
Atsushi
A
Migita
Kiyoshi
K
Bird
Phillip I
PI
Anderson
Paul
P
Eguchi
Katsumi
K
D017209:Apoptosis; D051023:BH3 Interacting Domain Death Agonist Protein; D018801:CD2 Antigens / Q000502:physiology; D002352:Carrier Proteins / Q000378:metabolism; D020169:Caspases / Q000502:physiology; D053804:Granzymes; D006801:Humans; D007694:Killer Cells, Natural / Q000502:physiology*; D008213:Lymphocyte Activation; D012697:Serine Endopeptidases / Q000032:analysis / Q000502:physiology*; D015843:Serpins / Q000032:analysis
D051023:BH3 Interacting Domain Death Agonist Protein; C494814:BID protein, human; D018801:CD2 Antigens; D002352:Carrier Proteins; C102316:SERPINB9 protein, human; D015843:Serpins; C509213:GZMB protein, human; D053804:Granzymes; D012697:Serine Endopeptidases; D020169:Caspases