Granzyme A activates another way to die.
Granzyme A (GzmA) is the most abundant serine protease in killer cell cytotoxic granules. GzmA activates a novel programed cell death pathway that begins in the mitochondrion, where cleavage of NDUFS3 in electron transport complex I disrupts mitochondrial metabolism and generates reactive oxygen species (ROS). ROS drives the endoplasmic reticulum-associated SET complex into the nucleus, where it activates single-stranded DNA damage. GzmA also targets other important nuclear proteins for degradation, including histones, the lamins that maintain the nuclear envelope, and several key DNA damage repair proteins (Ku70, PARP-1). Cells that are resistant to the caspases or GzmB by overexpressing bcl-2 family anti-apoptotic proteins or caspase or GzmB protease inhibitors are sensitive to GzmA. By activating multiple cell death pathways, killer cells provide better protection against a variety of intracellular pathogens and tumors. GzmA also has proinflammatory activity; it activates pro-interleukin-1beta and may also have other proinflammatory effects that remain to be elucidated.
Lieberman
Judy
J
Immune Disease Institute and Program in Cellular and Molecular Medicine, Children's Hospital Boston, Harvard Medical School, Boston, MA, USA. lieberman@idi.harvard.edu
D000818:Animals; D016923:Cell Death; D003602:Cytotoxicity, Immunologic / Q000187:drug effects; D053804:Granzymes / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism*; D006801:Humans; D018836:Inflammation Mediators / Q000378:metabolism; D011487:Protein Conformation; D022142:Secretory Vesicles / Q000201:enzymology / Q000276:immunology; D015842:Serine Proteinase Inhibitors / Q000378:metabolism / Q000494:pharmacology; D015398:Signal Transduction; D013329:Structure-Activity Relationship; D013602:T-Lymphocytes, Cytotoxic / Q000187:drug effects / Q000201:enzymology* / Q000276:immunology
D018836:Inflammation Mediators; D015842:Serine Proteinase Inhibitors; D053804:Granzymes