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

Nature Medicine volume 6, pages 1241–1247 (2000)Cite this article

Abstract

Dysregulation of apoptosis contributes to the pathogenesis of many human diseases. As effectors of the apoptotic machinery, caspases are considered potential therapeutic targets. Using an established in vivo model of Fas-mediated apoptosis, we demonstrate here that elimination of certain caspases was compensated in vivo by the activation of other caspases. Hepatocyte apoptosis and mouse death induced by the Fas agonistic antibody Jo2 required proapoptotic Bcl-2 family member Bid and used a Bid-mediated mitochondrial pathway of caspase activation; deficiency in caspases essential for this pathway, caspase-9 or caspase-3, unexpectedly resulted in rapid activation of alternate caspases after injection of Jo2, and therefore failed to protect mice against Jo2 toxicity. Moreover, both ultraviolet and gamma irradiation, two established inducers of the mitochondrial caspase-activation pathway, also elicited compensatory activation of caspases in cultured caspase-3−/− hepatocytes, indicating that the compensatory caspase activation was mediated through the mitochondria. Our findings provide direct experimental evidence for compensatory pathways of caspase activation. This issue should therefore be considered in developing caspase inhibitors for therapeutic applications.

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Figure 1: Lethal effect induced by injection of Jo2 in wild-type and caspase-deficient mice.
Figure 2: Delayed hemorrhage and endothelia destruction in caspase-3−/− liver after injection of Jo2.
Figure 3: Jo2-induced cytochrome c release, Bid translocation and caspase activation in wild-type and caspase deficient mice.
Figure 4: Jo2-induced compensatory caspase activation in caspase-3−/− and caspase-9−/− hepatocytes.
Figure 5: Compensatory caspase activation in caspase-3−/− hepatocytes in response to gamma and ultraviolet irradiation.
Figure 6: Mitochondria-dependent caspase-activating pathways after Fas signaling.

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Acknowledgements

We thank L. Evangelisti, C. Hughes and D. Butkus for embryonic stem cell culture and injection, K. Augustyn for primary hepatocyte isolation and F. Manzo for help in preparing this manuscript. This work was supported in part by National Institutes of Health grant 1 P30 DK34989 (T.S.Z.). S.H. is a recipient of the Lavoisier Program Fellowship (France) and is also supported by a fellowship from the Parkinson's Disease Foundation (New York, New York). Y.L. is partly supported by National Institutes of Health grant CA 13106-25. R.A.F. is an Investigator of the Howard Hughes Medical Institute.

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Author notes

  1. Timothy S. Zheng

    Present address: Biogen, 14 Cambridge Center, Cambridge, Massachusetts, 02142, USA

  2. Timothy S. Zheng and Stéphane Hunot: T.S.Z. and S.H. contributed equally to this work.

Authors and Affiliations

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

    Timothy S. Zheng, Stéphane Hunot & Richard A. Flavell

  2. Vertex Pharmaceuticals, 130 Waverly Street, Cambridge, 02139, Massachusetts, USA

    Keisuke Kuida

  3. Division of Developmental and Differentiation, National Institute of Neuroscience, NCNP, Kodaira, 187, Tokyo, Japan

    Takashi Momoi

  4. IDUN Pharmaceuticals, 11805 North Torrey Pines Road, La Jolla, 92037, California, USA

    Anu Srinivasan

  5. Merck Frosst Canada, PO Box 1005, Point-Claire-Dorval, Quebec, H9R 4P8

    Donald W. Nicholson

  6. Cold Spring Harbor Laboratory, 1 Bungtown Road, Cold Spring Harbor, New York, 11724, New York, USA

    Yuri Lazebnik

  7. Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, 06510, Connecticut, USA

    Richard A. Flavell

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Correspondence to Richard A. Flavell.

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Zheng, T., Hunot, S., Kuida, K. et al. Deficiency in caspase-9 or caspase-3 induces compensatory caspase activation. Nat Med 6, 1241–1247 (2000). https://doi.org/10.1038/81343

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