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Updated: Jul 16, 2026

Lighting Up the Pathways to Caspase Activation Using Bimolecular Fluorescence Complementation
08:47

Lighting Up the Pathways to Caspase Activation Using Bimolecular Fluorescence Complementation

Published on: March 5, 2018

Deficiency in caspase-9 or caspase-3 induces compensatory caspase activation

T S Zheng1, S Hunot, K Kuida

  • 1Section of Immunobiology, Yale University School of Medicine, New Haven, Connecticut 06510, USA.

Nature Medicine
|November 4, 2000
PubMed

Insights

Targeting caspases for disease therapy is complex. Eliminating specific caspases doesn

Area of Science:

  • Cellular biology
  • Molecular mechanisms of apoptosis

Background:

  • Dysregulation of apoptosis (programmed cell death) is implicated in numerous human diseases.
  • Caspases, as key executioners of apoptosis, represent significant therapeutic targets.

Purpose of the Study:

  • To investigate compensatory caspase activation in vivo using a Fas-mediated apoptosis model.
  • To assess the therapeutic implications of caspase compensatory pathways.

Main Methods:

  • Utilized an in vivo model of Fas-mediated apoptosis induced by the agonistic antibody Jo2.
  • Examined hepatocyte apoptosis and mouse survival in caspase-deficient models.
  • Investigated compensatory caspase activation in cultured hepatocytes exposed to UV and gamma irradiation.

Main Results:

  • Elimination of specific caspases (caspase-9 or caspase-3) did not prevent apoptosis or death in vivo.
  • Jo2-induced toxicity in caspase-deficient mice led to rapid activation of alternate caspases.
  • Mitochondrial pathways, including Bid-mediated activation, were involved in compensatory caspase activation.
  • UV and gamma irradiation also induced compensatory caspase activation in caspase-3 deficient hepatocytes.

Conclusions:

  • Direct experimental evidence supports the existence of compensatory caspase activation pathways.
  • Compensatory caspase activation is mediated through mitochondria.
  • These findings necessitate consideration of compensatory mechanisms when developing caspase inhibitors for therapeutic use.

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