Pro-caspase-3 is a major physiologic target of caspase-8

J Biol Chem. 1998 Oct 16;273(42):27084-90. doi: 10.1074/jbc.273.42.27084.


The apoptotic signal triggered by ligation of members of the death receptor family is promoted by sequential activation of caspase zymogens. We show here that in a purified system, the initiator caspases-8 and -10 directly process the executioner pro-caspase-3 with activation rates (kcat/Km) of 8.7 x 10(5) and 2.8 x 10(5) M-1 s-1, respectively. These rates are of sufficient magnitude to indicate direct processing in vivo. Differentially processed forms of caspase-3 that accumulate during its activation have similar rates of activation, activities, and specificities. The pattern and rate of caspase-8 induced activation of pro-caspase-3 in cytosolic extracts was the same as in a purified system. Moreover, immunodepletion of a putative intermediary in the pathway to activation, pro-caspase-9, was without consequence. Taken together these data demonstrate that the initiator caspase-8 can directly activate pro-caspase-3 without the requirement for an accelerator. The in vitro data thus help to deconvolute previous in vivo transfection studies which have debated the role of a direct versus indirect transmission of the apoptotic signal generated by ligation of death receptors.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Apoptosis
  • Caspase 10
  • Caspase 3
  • Caspase 8
  • Caspase 9
  • Caspases / genetics
  • Caspases / metabolism*
  • Cytosol / metabolism
  • Enzyme Activation
  • Enzyme Precursors / genetics
  • Enzyme Precursors / metabolism*
  • Granzymes
  • Kinetics
  • Models, Biological
  • Protein Processing, Post-Translational
  • Serine Endopeptidases / metabolism
  • Signal Transduction


  • Enzyme Precursors
  • Granzymes
  • Serine Endopeptidases
  • Caspase 10
  • Caspase 3
  • Caspase 8
  • Caspase 9
  • Caspases