Granzyme A activates another way to die

Immunol Rev. 2010 May;235(1):93-104. doi: 10.1111/j.0105-2896.2010.00902.x.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Review

MeSH terms

  • Animals
  • Cell Death
  • Cytotoxicity, Immunologic* / drug effects
  • Granzymes / antagonists & inhibitors
  • Granzymes / chemistry
  • Granzymes / metabolism*
  • Humans
  • Inflammation Mediators / metabolism
  • Protein Conformation
  • Secretory Vesicles / enzymology
  • Secretory Vesicles / immunology
  • Serine Proteinase Inhibitors / metabolism
  • Serine Proteinase Inhibitors / pharmacology
  • Signal Transduction
  • Structure-Activity Relationship
  • T-Lymphocytes, Cytotoxic / drug effects
  • T-Lymphocytes, Cytotoxic / enzymology*
  • T-Lymphocytes, Cytotoxic / immunology


  • Inflammation Mediators
  • Serine Proteinase Inhibitors
  • Granzymes