Cleavage of FLICE (caspase-8) by granzyme B during cytotoxic T lymphocyte-induced apoptosis

Jan Paul Medema, René E M Toes, Carsten Scaffidi, Timothy S. Zheng, Richard A. Flavell, Cornelius J M Melief, Marcus E. Peter, Rienk Offringa, Peter H. Krammer*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

112 Scopus citations

Abstract

Cytotoxic T lymphocytes induce apoptosis in target cells through the CD95(APO-1/Fas) and the perforin/granzyme B (GrB) pathway. The exact substrate of GrB in vivo is still unknown, but to induce apoptosis GrB requires the activity of caspases in target cells. We show here that in Hela target cells induction of apoptosis through the perforin/GrB pathway resulted in minor direct cleavage of CPP32 (caspase-3) by GrB. Most caspase-3 cleavage resulted from activation of an upstream caspase. Moreover, target cells derived from caspase-3(-/-) mice displayed GrB-induced poly(ADP-ribose) polymerase (PARP) cleavage with only partially reduced efficiency compared to wild-type target cells. This indicates that other PARP-cleaving caspases can be activated during perforin/GrB-induced cell death. In contrast to caspase-3, FLICE (caspase-8) was directly cleaved by GrB in HeLa cells. We therefore conclude that FLICE not only plays a central role in CD95(APO-1/Fas)-induced apoptosis but can also be directly activated during perforin/GrB-induced apoptosis.

Original languageEnglish (US)
Pages (from-to)3492-3498
Number of pages7
JournalEuropean Journal of Immunology
Volume27
Issue number12
DOIs
StatePublished - Dec 1 1997

Keywords

  • Apoptosis
  • Caspase-8
  • Cytotoxicity
  • FLICE
  • Granzyme B
  • Perforin

ASJC Scopus subject areas

  • Immunology

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