The FLIP Side of Life

Sci Signal. 2013 Jan 15;6(258):pe2. doi: 10.1126/scisignal.2003845.

Abstract

The anti-apoptotic protein c-FLIP, a catalytically inactive homolog of caspase-8, is an important regulator of death receptor signaling. Death receptors constitute a subgroup of the tumor necrosis factor receptor (TNFR) superfamily, which includes TNFR1, Fas, DR4, and DR5. When activated by their respective ligands, TNF, Fas ligand (FasL), and TNF-related apoptosis-inducing ligand (TRAIL), these receptors cause caspase-8-mediated apoptosis. If caspase-8 activity is blocked, however, then these receptors promote death by necroptosis (programmed necrosis), which requires the kinases receptor-interacting kinase 1 (RIPK1) and RIPK3, as well as mixed-lineage kinase-like protein. Necroptosis has become the subject of intense research because it promotes inflammation, and inhibiting this pathway can limit extensive tissue damage and even lethality in inflammatory syndromes. A study now reports on the role of c-FLIP in vivo from experiments with a range of conditional knockout mice and demonstrates that c-FLIP plays a critical role in inhibiting both apoptotic and necroptotic cell death within the whole mouse.

MeSH terms

  • Animals
  • Apoptosis
  • CASP8 and FADD-Like Apoptosis Regulating Protein / genetics
  • CASP8 and FADD-Like Apoptosis Regulating Protein / metabolism*
  • Caspase 8 / metabolism
  • Humans
  • Ligands
  • Mice
  • Mice, Knockout
  • Models, Biological
  • Mutation
  • Receptors, TNF-Related Apoptosis-Inducing Ligand / metabolism
  • Receptors, Tumor Necrosis Factor / metabolism*
  • Receptors, Tumor Necrosis Factor, Type I / metabolism
  • Signal Transduction*
  • fas Receptor / metabolism

Substances

  • CASP8 and FADD-Like Apoptosis Regulating Protein
  • CFLAR protein, human
  • Cflar protein, mouse
  • Ligands
  • Receptors, TNF-Related Apoptosis-Inducing Ligand
  • Receptors, Tumor Necrosis Factor
  • Receptors, Tumor Necrosis Factor, Type I
  • fas Receptor
  • Caspase 8