Granzyme H induces apoptosis of target tumor cells characterized by DNA fragmentation and Bid-dependent mitochondrial damage.
Natural killer (NK) cells are the effectors of innate immunity to act as the first line of defense against viruses and tumors. Granzyme H (GzmH) is predicted to evolve from GzmB and constitutively expressed at a high level in human NK cells. It indicates GzmH plays a pivotal role in NK cell mediated cytolysis. However GzmH is defined as an orphan granzyme and its function has less been defined. Here we demonstrate GzmH can induce rapid apoptosis of target cells, which is dependent on caspase activation and mitochondrial damage. GzmH-induced death is characterized by phophatidylserine externalization, nuclear condensation, DNA fragmentation, caspase activation and cytochrome c release that are hallmarks of typical apoptosis. GzmH can directly cleave ICAD to unleash CAD for DNA fragmentation. Moreover, GzmH directly processes Bid to produce the active form tBid leading to cytochrome c release. Therefore, GzmH may play an essential role in caspase-dependent pathogen clearance in the innate immunity that may complement the proapoptotic function of GzmB in human NK cells.
Hou
Qiang
Q
National Laboratory of Biomacromolecules, Center for Infection and Immunity, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China.
Zhao
Tongbiao
T
Zhang
Honglian
H
Lu
Hongxia
H
Zhang
Qixiang
Q
Sun
Lei
L
Fan
Zusen
Z
D017209:Apoptosis; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism; D051023:BH3 Interacting Domain Death Agonist Protein / Q000378:metabolism*; D020169:Caspases / Q000378:metabolism; D045304:Cytochromes c / Q000378:metabolism; D053938:DNA Fragmentation; D004789:Enzyme Activation; D053804:Granzymes / Q000494:pharmacology / Q000502:physiology*; D006367:HeLa Cells; D006801:Humans; D019169:Jurkat Cells; D008928:Mitochondria / Q000235:genetics / Q000502:physiology*; D010718:Phosphatidylserines / Q000378:metabolism; D010843:Pichia / Q000235:genetics; D011994:Recombinant Proteins / Q000494:pharmacology
D051017:Apoptosis Regulatory Proteins; D051023:BH3 Interacting Domain Death Agonist Protein; C494814:BID protein, human; D010718:Phosphatidylserines; D011994:Recombinant Proteins; C109664:caspase-activated DNase inhibitor; D045304:Cytochromes c; C069434:GZMH protein, human; D053804:Granzymes; D020169:Caspases