Activation of an interleukin 1 converting enzyme-dependent apoptosis pathway by granzyme B

Lianfa Shi, Gao Chen, Glen Macdonald, Louise Bergeron, Honglin Li, Masayuki Miura, Rocco J. Rotello, Douglas K. Miller, Ping Li, Tara Seshadri, Junying Yuan, Arnold H. Greenberg

Research output: Contribution to journalArticle

73 Scopus citations

Abstract

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 1β 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 lch-IS that exhibit resistance to granzyme B, CPP32 is processed to pl7 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, p34(cdc2) 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.

Original languageEnglish (US)
Pages (from-to)11002-11007
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume93
Issue number20
DOIs
StatePublished - Oct 1 1996

Keywords

  • CPP32
  • Fas
  • Ich-IS
  • poly(ADP-ribose) polymerase

ASJC Scopus subject areas

  • General

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    Shi, L., Chen, G., Macdonald, G., Bergeron, L., Li, H., Miura, M., Rotello, R. J., Miller, D. K., Li, P., Seshadri, T., Yuan, J., & Greenberg, A. H. (1996). Activation of an interleukin 1 converting enzyme-dependent apoptosis pathway by granzyme B. Proceedings of the National Academy of Sciences of the United States of America, 93(20), 11002-11007. https://doi.org/10.1073/pnas.93.20.11002