Granzyme A activates another way to die

作者：Lieberman Judy^*

来源：Immunological Reviews, 2010, 235(1): 93-104.

DOI：10.1111/j.0105-2896.2010.00902.x

• granzyme A
• cytotoxic T cell
• SET complex
• NDUFS3
• NM23-H1
• TREX1

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-1 beta and may also have other proinflammatory effects that remain to be elucidated.

• 出版日期2010-5