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Activation of the apoptotic protease CPP32 by cytotoxic T-cell-derived granzyme B

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Abstract

CYTOTOXIC T lymphocyte (CTL)-mediated cytotoxicity represents the body's major defence against virus-infected and tumorigenic cells, and contributes to transplant rejection and autoimmune disease. During killing, CTL granules are exocytosed, releasing their contents into the intercellular space between the target cell and the effector. Perform facilitates the entry of cytotoxic cell serine proteases, the granzymes, into the target cell, where they induce apoptotic death by an unknown pathway1. Granzyme B is essential for the induction of DNA fragmentation and apoptosis in target cells2-5, yet its substrate is unknown. Identification of the intracellular substrate for granzyme B is therefore the key to understanding the mechanism of CTL-mediated killing. Here we show that granzyme B cleaves and activates CPP32, the precursor of the protease responsible for cleavage of poly(ADP-ribose) polymerase.

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Authors and Affiliations

  1. Department of Biochemistry, University of Alberta, Edmonton, Alberta, T6G 2H7, Canada

    Alison J. Darmon & R. Chris Bleackley

  2. Department of Biochemistry and Molecular Biology, Merck Frosst Centre for Therapeutic Research, PO Box 1005, Pointe Claire-Dorval, Quebec, H9R 4P8, Canada

    Donald W. Nicholson

Authors
  1. Alison J. Darmon
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  2. Donald W. Nicholson
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  3. R. Chris Bleackley
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Darmon, A., Nicholson, D. & Bleackley, R. Activation of the apoptotic protease CPP32 by cytotoxic T-cell-derived granzyme B. Nature 377, 446–448 (1995). https://doi.org/10.1038/377446a0

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  • DOI: https://doi.org/10.1038/377446a0

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