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Granzyme A activates another way to die
Author(s) -
Lieberman Judy
Publication year - 2010
Publication title -
immunological reviews
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 6.839
H-Index - 223
eISSN - 1600-065X
pISSN - 0105-2896
DOI - 10.1111/j.0105-2896.2010.00902.x
Subject(s) - granzyme , microbiology and biotechnology , biology , proinflammatory cytokine , granzyme a , cytotoxic t cell , granzyme b , caspase , mitochondrion , programmed cell death , apoptosis , perforin , immunology , biochemistry , inflammation , in vitro
Summary: 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‐1β and may also have other proinflammatory effects that remain to be elucidated.