Granzyme K directly processes bid to release cytochrome c and endonuclease G leading to mitochondria-dependent cell death.
Granule-mediated cytolysis is the major pathway for killer lymphocytes to kill pathogens and tumor cells. Little is known about how granzyme K functions in killer lymphocyte-mediated cytolysis. We previously showed that human GzmK triggers rapid cell death independently of caspase activation with single-stranded DNA nicks, similar to GzmA. In this study we found that GzmK can induce rapid reactive oxygen species generation and collapse of mitochondrial inner membrane potential (DeltaPsim). Blockade of reactive oxygen species production by antioxidant N-acetylcysteine or superoxide scavenger Tiron inhibits GzmK-induced cell death. Moreover GzmK targets mitochondria by cleaving Bid to generate its active form tBid, which disrupts the outer mitochondrial membrane leading to the release of cytochrome c and endonuclease G. Thus, we showed herein that GzmK-induced caspase-independent death occurs through Bid-dependent mitochondrial damage that is different from GzmA.
Zhao
Tongbiao
T
National Laboratory of Biomacromolecules and Center for Infection and Immunity, Institute of Biophysics, Chinese Academy of Sciences, 15 Datun Road, Beijing 100101, China.
Zhang
Honglian
H
Guo
Yuming
Y
Fan
Zusen
Z
D000818:Animals; D051023:BH3 Interacting Domain Death Agonist Protein / Q000378:metabolism; D016923:Cell Death; D045304:Cytochromes c / Q000378:metabolism*; D004706:Endodeoxyribonucleases / Q000737:chemistry*; D004789:Enzyme Activation; D053804:Granzymes / Q000737:chemistry* / Q000378:metabolism; D006367:HeLa Cells; D006801:Humans; D019169:Jurkat Cells; D051379:Mice; D008928:Mitochondria / Q000378:metabolism*; D011485:Protein Binding; D017382:Reactive Oxygen Species
D051023:BH3 Interacting Domain Death Agonist Protein; D017382:Reactive Oxygen Species; D045304:Cytochromes c; D004706:Endodeoxyribonucleases; C052391:endonuclease G; D053804:Granzymes