C-FLIPL is a dual function regulator for caspase-8 activation and CD95-mediated apoptosis

David W. Chang, Zheng Xing, Yi Pan, Alicia Algeciras-Schimnich, Bryan C. Barnhart, Shoshanit Yaish-Ohad, Marcus E. Peter, Xiaolu Yang

Research output: Contribution to journalArticlepeer-review

446 Scopus citations

Abstract

Activation of the caspase cascade is a pivotal step in apoptosis and can occur via death adaptor-mediated homo-oligomerization of initiator procaspases. Here we show that c-FLIPL, a protease-deficient caspase homolog widely regarded as an apoptosis inhibitor, is enriched in the CD95 death-inducing signaling complex (DISC) and potently promotes procaspase-8 activation through hetero-dimerization. c-FLIPL exerts its effect through its protease-like domain, which associates efficiently with the procaspase-8 protease domain and induces the enzymatic activity of the zymogen. Ectopic expression of c-FLIPL at physiologically relevant levels enhances procaspase-8 processing in the CD95 DISC and promotes apoptosis, while a decrease of c-FLIPL expression results in inhibition of apoptosis. c-FLIPL acts as an apoptosis inhibitor only at high ectopic expression levels. Thus, c-FLIPL defines a novel type of caspase regulator, distinct from the death adaptors, that can either promote or inhibit apoptosis.

Original languageEnglish (US)
Pages (from-to)3704-3714
Number of pages11
JournalEMBO Journal
Volume21
Issue number14
DOIs
StatePublished - Jul 15 2002

Keywords

  • Apoptosis
  • C-FLIP
  • CD95 (Fas/APO-1)
  • Caspase activation
  • Caspase-8

ASJC Scopus subject areas

  • Neuroscience(all)
  • Molecular Biology
  • Biochemistry, Genetics and Molecular Biology(all)
  • Immunology and Microbiology(all)

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