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.
Immune Disease Institute and Program in Cellular and Molecular Medicine, Children's Hospital Boston, Harvard Medical School, Boston, MA, USA. lieberman@idi.harvard.edu
Judy
J
Lieberman
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