Granzyme B-induced apoptosis requires both direct caspase activation and relief of caspase inhibition

Immunity. 2003 Mar;18(3):355-65. doi: 10.1016/s1074-7613(03)00032-3.


Cytotoxic lymphocytes employ Granzyme B as a potent initiator of apoptosis to cleave and activate effector caspases. Unexpectedly, cells transfected with Bcl-2 were resistant to granzyme B-induced killing, suggesting that a mitochondrial pathway was critical. Utilizing cells expressing a dominant-negative caspase 9, the current study demonstrated that caspase activation via the apoptosome was not required. Indeed, cleavage of caspase 3 to p20 still occurred in Bcl-2-transfectants but processing to p17 was blocked. This blockade was recapitulated by the Inhibitor-of-Apoptosis-Protein XIAP and relieved by Smac/DIABLO. Thus granzyme B mediates direct cleavage of caspase 3 and also activates mitochondrial disruption, resulting in the release of proapoptotic proteins that suppress caspase inhibition. Engagement of both pathways is critical for granzyme-induced killing.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Apoptosis / immunology
  • Apoptosis / physiology*
  • Apoptosis Regulatory Proteins
  • Carrier Proteins / metabolism
  • Caspase 3
  • Caspase 9
  • Caspase Inhibitors
  • Caspases / metabolism*
  • Enzyme Activation
  • Enzyme Precursors / metabolism
  • Genes, bcl-2
  • Granzymes
  • Humans
  • Intracellular Signaling Peptides and Proteins
  • Jurkat Cells
  • Mitochondrial Proteins / metabolism
  • Models, Biological
  • Protein Processing, Post-Translational
  • Proteins / metabolism
  • Serine Endopeptidases / metabolism*
  • Transfection
  • X-Linked Inhibitor of Apoptosis Protein


  • Apoptosis Regulatory Proteins
  • Carrier Proteins
  • Caspase Inhibitors
  • DIABLO protein, human
  • Enzyme Precursors
  • Intracellular Signaling Peptides and Proteins
  • Mitochondrial Proteins
  • Proteins
  • X-Linked Inhibitor of Apoptosis Protein
  • XIAP protein, human
  • GZMB protein, human
  • Granzymes
  • Serine Endopeptidases
  • CASP3 protein, human
  • CASP9 protein, human
  • Caspase 3
  • Caspase 9
  • Caspases