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Activation of an Interleukin 1 Converting Enzyme Dependent Apoptosis Pathway by Granzyme B
Proceedings of the National Academy of Sciences
  • Lianfa Shi, University of Manitoba
  • Gao Chen, University of Manitoba
  • Glen MacDonald, University of Manitoba
  • Loise Bergeron, Massachusetts General Hospital
  • Honglin Li, Massachusetts General Hospital
  • Masayuki Miura, Massachusetts General Hospital
  • Rocco J. Rotello, Cedarville University
  • Douglas K. Miller, Merck Research Laboratories
  • Ping Li, BASF Bioresearch Corporation
  • Tara Seshadri, BASF Bioresearch Corporation
  • Junying Yuan, Massachusetts General Hospital
  • Arnold H. Greenberg, University of Manitoba
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Cytotoxic T lymphocytes (CTL) can induce apoptosis through a granzyme B-based killing mechanism. Here we show that in cells undergoing apoptosis by granzyme B, both p45 pro-interleukin 1 beta converting enzyme (ICE) and pro-CPP32 are processed. Using ICE deficient (ICE -/-) mice, embryonic fibroblasts exhibit high levels of resistance to apoptosis by granzyme B or granzyme 3, while B lymphoblasts are granzyme B-resistant, thus identifying an ICE-dependent apoptotic pathway that is activated by CTL granzymes. In contrast, an alternative ICE-independent pathway must also be activated as ICE -/- thymocytes remain susceptible to apoptosis by both granzymes. In ICE -/- B cells or HeLa cells transfected with mutant inactive ICE or Ich-1S that exhibit resistance to granzyme B, CPP32 is processed to p17 and poly(ADP-ribose) polymerase is cleaved indicating that this protease although activated was not associated with an apoptotic nuclear phenotype. Using the peptide inhibitor Ac-DEVD-CHO, apoptosis as well as p45 ICE hydrolysis are suppressed in HeLa cells, suggesting that a CPP32-like protease is upstream of ICE. In contrast, p34cdc2 kinase, which is required for granzyme B-induced apoptosis, remains inactive in ICE -/- B cells indicating it is downstream of ICE. We conclude that granzyme B activates an ICE-dependent cell death pathway in some cell types and requires a CPP32-like Ac-DEVD-CHO inhibitable protease acting upstream to initiate apoptosis.
  • Interleukin,
  • enzyme,
  • apoptosis,
  • Granzyme B
Citation Information
Lianfa Shi, Gao Chen, Glen MacDonald, Loise Bergeron, et al.. "Activation of an Interleukin 1 Converting Enzyme Dependent Apoptosis Pathway by Granzyme B" Proceedings of the National Academy of Sciences Vol. 93 Iss. 20 (1996) p. 11002 - 11007
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