title: Granzyme B leakage-induced cell death: a new type of activation-induced natural killer cell death.
abstract: 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.
authors.affiliation: First Department of Internal Medicine, Nagasaki University School of Medicine, Nagasaki, Japan. idah@net.nagasaki-u.ac.jp
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Ida
authors.forename: Tomoki
authors.initials: T
authors.lastname: Nakashima
authors.forename: Nancy L
authors.initials: NL
authors.lastname: Kedersha
authors.forename: Satoshi
authors.initials: S
authors.lastname: Yamasaki
authors.forename: Mingguo
authors.initials: M
authors.lastname: Huang
authors.forename: Yasumori
authors.initials: Y
authors.lastname: Izumi
authors.forename: Taiichiro
authors.initials: T
authors.lastname: Miyashita
authors.forename: Tomoki
authors.initials: T
authors.lastname: Origuchi
authors.forename: Atsushi
authors.initials: A
authors.lastname: Kawakami
authors.forename: Kiyoshi
authors.initials: K
authors.lastname: Migita
authors.forename: Phillip I
authors.initials: PI
authors.lastname: Bird
authors.forename: Paul
authors.initials: P
authors.lastname: Anderson
authors.forename: Katsumi
authors.initials: K
authors.lastname: Eguchi
mesh_terms: 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
chemical_list: 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