Selective chemical functional probes of granzymes A and B reveal granzyme B is a major effector of natural killer cell-mediated lysis of target cells

Chem Biol. 2005 May;12(5):567-77. doi: 10.1016/j.chembiol.2005.03.006.


The mechanism of target cell lysis in cytotoxic lymphocyte-mediated death is not well understood, and the role of granzymes in this process is unclear. Chemical functional probes were thus prepared for the major granzymes A and B to deconvolute their role in natural killer cell-mediated lysis of target cells. These biotinylated and substrate specificity-based diphenyl phosphonates allowed facile evaluation of selectivity through activity-based profiling in cell lysates and intact cells. Both inhibitors were found to be extremely selective in vitro and in cells. Use of these inhibitors in cell-based assays revealed granzyme A to be a minor effector and granzyme B to be a major effector of target cell lysis by natural killer cells. These studies indicate that the proapoptotic granzyme B functions also as a pronecrotic effector of target cell death.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Apoptosis
  • Avidin / metabolism
  • Cell Death
  • Cell Line
  • Granzymes
  • Humans
  • K562 Cells
  • Killer Cells, Natural / enzymology*
  • Organophosphorus Compounds / chemical synthesis
  • Organophosphorus Compounds / pharmacology
  • Serine Endopeptidases / metabolism*
  • Serine Proteinase Inhibitors / chemical synthesis
  • Serine Proteinase Inhibitors / pharmacology*


  • Organophosphorus Compounds
  • Serine Proteinase Inhibitors
  • Avidin
  • GZMB protein, human
  • Granzymes
  • Serine Endopeptidases
  • GZMA protein, human