Essential Requirement for caspase-8/FLICE in the Initiation of the Fas-induced Apoptotic Cascade

Curr Biol. 1998 Sep 10;8(18):1001-8. doi: 10.1016/s0960-9822(07)00420-4.

Abstract

Background: Fas (APO-1/CD95) is a member of the tumor necrosis factor receptor (TNF-R) family and induces apoptosis when crosslinked with either Fas ligand or agonistic antibody (Fas antibody). The Fas-Fas ligand system has an important role in the immune system where it is involved in the downregulation of immune responses and the deletion of peripheral autoreactive T lymphocytes. The intracellular domain of Fas interacts with several proteins including FADD (MORT-1), DAXX, RIP, FAF-1, FAP-1 and Sentrin. The adaptor protein FADD can, in turn, interact with the cysteine protease caspase-8 (FLICE/MACH/Mch5).

Results: In a genetic screen for essential components of the Fas-mediated apoptotic cascade, we isolated a Jurkat T lymphocyte cell line deficient in caspase-8 that was completely resistant to Fas-induced apoptosis. Complementation of this cell line with wild-type caspase-8 restored Fas-mediated apoptosis. Fas activation of multiple caspases and of the stress kinase p38 and c-Jun NH2-terminal kinase (JNK) was completely blocked in the caspase-8-deficient cell line. Furthermore, the cell line was severely deficient in cell death induced by TNF-alpha and was partially deficient in cell death induced by ultraviolet irradiation, adriamycin and etoposide.

Conclusions: This study provides the first genetic evidence that caspase-8 occupies an essential and apical position in the Fas signaling pathway and suggests that caspase-8 may participate broadly in multiple apoptotic pathways.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Apoptosis / drug effects
  • Apoptosis / physiology*
  • Apoptosis / radiation effects
  • Calcium-Calmodulin-Dependent Protein Kinases / metabolism
  • Caspase 8
  • Caspase 9
  • Caspases / metabolism*
  • Doxorubicin / pharmacology
  • Etoposide / pharmacology
  • Fas Ligand Protein
  • Humans
  • JNK Mitogen-Activated Protein Kinases
  • Jurkat Cells
  • Membrane Glycoproteins / physiology*
  • Mitogen-Activated Protein Kinases*
  • Reverse Transcriptase Polymerase Chain Reaction
  • Signal Transduction
  • Staurosporine / pharmacology
  • Tumor Necrosis Factor-alpha / pharmacology
  • Tumor Necrosis Factor-alpha / physiology
  • Ultraviolet Rays
  • fas Receptor / physiology*
  • p38 Mitogen-Activated Protein Kinases

Substances

  • FASLG protein, human
  • Fas Ligand Protein
  • Membrane Glycoproteins
  • Tumor Necrosis Factor-alpha
  • fas Receptor
  • Etoposide
  • Doxorubicin
  • Calcium-Calmodulin-Dependent Protein Kinases
  • JNK Mitogen-Activated Protein Kinases
  • Mitogen-Activated Protein Kinases
  • p38 Mitogen-Activated Protein Kinases
  • CASP8 protein, human
  • CASP9 protein, human
  • Caspase 8
  • Caspase 9
  • Caspases
  • Staurosporine