Nuclear war: the granzyme A-bomb.
Granzyme A, a serine protease in the cytotoxic granules of natural killer cells and cytotoxic T lymphocytes, induces caspase-independent cell death when introduced into target cells by perforin. Granzyme A induces single-stranded DNA damage as well as rapid loss of cell membrane integrity and mitochondrial transmembrane potential through unknown mechanisms. Granzyme A destroys the nuclear envelope by targeting lamins and opens up DNA for degradation by targeting histones. A special target of the granzyme A cell death pathway is an endoplasmic reticulum-associated complex, called the SET complex, which contains three granzyme A substrates, the nucleosome assembly protein SET, the DNA bending protein HMG-2, and the base excision repair endonuclease Ape1. The SET complex also contains the tumor suppressor protein pp32 and the granzyme A-activated DNase NM23-H1, which is inhibited by SET. Granzyme A cleavage of SET releases the inhibition and unleashes NM23-H1. Cleavage of Ape1 by granzyme A interferes with the ability of the target cell to repair itself. The novel cell death pathway initiated by granzyme A provides a parallel pathway for apoptosis, important in destroying targets that overexpress bcl-2 or are otherwise invulnerable to the caspases.
D000818:Animals; D016923:Cell Death; D002868:Chromosomal Proteins, Non-Histone; D004249:DNA Damage / Q000187:drug effects; D004268:DNA-Binding Proteins; D053804:Granzymes; D056488:Histone Chaperones; D006657:Histones / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D034882:Lamins / Q000187:drug effects / Q000378:metabolism; D008562:Membrane Glycoproteins / Q000378:metabolism; D051379:Mice; D054353:Perforin; D052899:Pore Forming Cytotoxic Proteins; D011506:Proteins / Q000378:metabolism / Q000502:physiology; D012697:Serine Endopeptidases / Q000494:pharmacology*; D013602:T-Lymphocytes, Cytotoxic / Q000201:enzymology; D014157:Transcription Factors
D002868:Chromosomal Proteins, Non-Histone; D004268:DNA-Binding Proteins; D056488:Histone Chaperones; D006657:Histones; D034882:Lamins; D008562:Membrane Glycoproteins; D052899:Pore Forming Cytotoxic Proteins; D011506:Proteins; C513473:SET protein, human; D014157:Transcription Factors; D054353:Perforin; D053804:Granzymes; D012697:Serine Endopeptidases; C509212:GZMA protein, human