Granzyme K cleaves the nucleosome assembly protein SET to induce single-stranded DNA nicks of target cells.
Although granzymes (Gzms) A- and B-induced cell death pathways have been defined, little is known about how other orphan Gzms function in CTL-mediated cytotoxicity. GzmK and A are tryptases among all the Gzms of humans and they are closely linked on the same chromosome. In this study, we showed that GzmK can be efficiently delivered into target cells with a cationic lipid protein transfection reagent Pro-Ject. We found human GzmK triggers rapid cell death independently of caspase activation. The features of death are characterized by rapid externalization of phosphatidylserine, nuclear morphological changes and single-stranded DNA nicks. GzmK hydrolyzes the nucleosome assembly protein SET in its recombinant and native forms or in intact cells. Cleavage of SET by GzmK abrogates its nucleosome assembly activity. After GzmK loading, SET and DNase NM23H1 rapidly translocate into the nucleus and SET is cleaved, where the nuclease activity of NM23H1 is activated to nick chromosomal DNA.
Zhao
T
T
National Laboratory of Biomacromolecules and Center for Infection and Immunity, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China.
Zhang
H
H
Guo
Y
Y
Zhang
Q
Q
Hua
G
G
Lu
H
H
Hou
Q
Q
Liu
H
H
Fan
Z
Z
D020169:Caspases / Q000378:metabolism / Q000502:physiology; D016923:Cell Death; D002467:Cell Nucleus / Q000201:enzymology / Q000502:physiology; D002868:Chromosomal Proteins, Non-Histone / Q000378:metabolism* / Q000502:physiology; D003594:Cytoplasmic Granules / Q000201:enzymology / Q000502:physiology*; D053904:DNA Breaks, Single-Stranded; D004268:DNA-Binding Proteins; D015971:Gene Expression Regulation, Enzymologic; D053804:Granzymes / Q000235:genetics / Q000378:metabolism*; D006367:HeLa Cells; D056488:Histone Chaperones; D006801:Humans; D054778:NM23 Nucleoside Diphosphate Kinases; D009701:Nucleoside-Diphosphate Kinase / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism* / Q000502:physiology; D014162:Transfection
D002868:Chromosomal Proteins, Non-Histone; D004268:DNA-Binding Proteins; D056488:Histone Chaperones; D054778:NM23 Nucleoside Diphosphate Kinases; C513473:SET protein, human; D014157:Transcription Factors; D009701:Nucleoside-Diphosphate Kinase; D053804:Granzymes; D020169:Caspases