Induction of rapid histone degradation by the cytotoxic T lymphocyte protease Granzyme A.
The cytotoxic T lymphocyte protease granzyme A induces caspase-independent cell death in which DNA single-strand nicking is observed instead of oligonucleosomal fragmentation. Granzyme A is a specific tryptase that concentrates in the nucleus of targeted cells and synergistically enhances DNA fragmentation induced by the caspase activator granzyme B. Here we show that granzyme A treatment of isolated nuclei enhances DNA accessibility to exogenous endonucleases. In vitro and after cell loading with perforin, GrnA completely degrades histone H1 and cleaves core histones into approximately 16-kDa fragments. Histone digestion provides a mechanism for unfolding compacted chromatin and facilitating endogenous DNase access to DNA during T cell and natural killer cell granule-mediated apoptosis.
Zhang
D
D
Center for Blood Research, Massachusetts General Hospital and Department of Pediatrics, Harvard Medical School, Boston, Massachusetts 02115, USA.
Pasternack
M S
MS
Beresford
P J
PJ
Wagner
L
L
Greenberg
A H
AH
Lieberman
J
J
D000818:Animals; D001426:Bacterial Proteins / Q000378:metabolism; D019556:COS Cells; D061945:Caspase Inhibitors; D020169:Caspases / Q000378:metabolism; D002467:Cell Nucleus / Q000378:metabolism; D002843:Chromatin / Q000378:metabolism; D004247:DNA / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism; D003851:Deoxyribonucleases / Q000378:metabolism; D053804:Granzymes; D018922:HL-60 Cells; D006493:Heparin / Q000031:analogs & derivatives / Q000378:metabolism; D006657:Histones / Q000378:metabolism*; D006801:Humans; D020014:K562 Cells; D008562:Membrane Glycoproteins / Q000378:metabolism; D054353:Perforin; D052899:Pore Forming Cytotoxic Proteins; D017434:Protein Structure, Tertiary / Q000502:physiology; D011509:Proteoglycans / Q000378:metabolism; D012697:Serine Endopeptidases / Q000378:metabolism*; D013379:Substrate Specificity; D013602:T-Lymphocytes, Cytotoxic / Q000201:enzymology* / Q000378:metabolism; D014357:Trypsin / Q000378:metabolism
D001426:Bacterial Proteins; D061945:Caspase Inhibitors; D002843:Chromatin; D004268:DNA-Binding Proteins; D006657:Histones; D008562:Membrane Glycoproteins; C118828:PHAP protein, Bacteria; D052899:Pore Forming Cytotoxic Proteins; D011509:Proteoglycans; C036090:heparin proteoglycan; D054353:Perforin; D006493:Heparin; D004247:DNA; D003851:Deoxyribonucleases; D053804:Granzymes; D012697:Serine Endopeptidases; D014357:Trypsin; C509212:GZMA protein, human; D020169:Caspases