title: Granzyme M directly cleaves inhibitor of caspase-activated DNase (CAD) to unleash CAD leading to DNA fragmentation.
abstract: Granzyme (Gzm)M is constitutively highly expressed in NK cells that may play a critical role in NK cell-mediated cytolysis. However, the function of GzmM has been less defined. Just one report showed GzmM induces a caspase-independent death pathway. In this study, we demonstrate a protein transfection reagent Pro-Ject can efficiently transport GzmM into target cells. GzmM initiates caspase-dependent apoptosis with typical apoptotic nuclear morphology. GzmM induces DNA fragmentation, not DNA nicking. GzmM can directly degrade inhibitor of caspase-activated DNase to release the nuclease activity of caspase-activated DNase for damaging DNA. Furthermore, GzmM cleaves the DNA damage sensor enzyme poly(ADP-ribose) polymerase to prevent cellular DNA repair and force apoptosis.
authors.affiliation: National Laboratory of Biomacromolecules and Center for Infection and Immunity, Institute of Biophysics, Chinese Academy of Sciences, 15 Datun Road, Beijing 100101, China.
authors.forename: Hongxia
authors.initials: H
authors.lastname: Lu
authors.forename: Qiang
authors.initials: Q
authors.lastname: Hou
authors.forename: Tongbiao
authors.initials: T
authors.lastname: Zhao
authors.forename: Honglian
authors.initials: H
authors.lastname: Zhang
authors.forename: Qixiang
authors.initials: Q
authors.lastname: Zhang
authors.forename: Lianfeng
authors.initials: L
authors.lastname: Wu
authors.forename: Zusen
authors.initials: Z
authors.lastname: Fan
mesh_terms: D017209:Apoptosis / Q000235:genetics / Q000276:immunology; D051017:Apoptosis Regulatory Proteins; D020169:Caspases / Q000502:physiology; D016923:Cell Death / Q000235:genetics / Q000276:immunology; D002467:Cell Nucleus / Q000201:enzymology / Q000235:genetics; D053938:DNA Fragmentation / Q000235:genetics / Q000276:immunology; D004277:DNA, Single-Stranded / Q000378:metabolism; D003851:Deoxyribonucleases / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000378:metabolism*; D053804:Granzymes; D006801:Humans; D006868:Hydrolysis; D019169:Jurkat Cells; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D021381:Protein Transport / Q000235:genetics / Q000276:immunology; D011506:Proteins / Q000378:metabolism*; D012697:Serine Endopeptidases / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology; D014162:Transfection
chemical_list: D051017:Apoptosis Regulatory Proteins; D004277:DNA, Single-Stranded; D004791:Enzyme Inhibitors; D011506:Proteins; C109664:caspase-activated DNase inhibitor; D011065:Poly(ADP-ribose) Polymerases; D003851:Deoxyribonucleases; C109663:caspase-activated deoxyribonuclease; C509218:GZMM protein, human; D053804:Granzymes; D012697:Serine Endopeptidases; D020169:Caspases