Fas triggers an alternative, caspase-8-independent cell death pathway using the kinase RIP as effector molecule

Nat Immunol. 2000 Dec;1(6):489-95. doi: 10.1038/82732.

Abstract

Cell death is achieved by two fundamentally different mechanisms: apoptosis and necrosis. Apoptosis is dependent on caspase activation, whereas the caspase-independent necrotic signaling pathway remains largely uncharacterized. We show here that Fas kills activated primary T cells efficiently in the absence of active caspases, which results in necrotic morphological changes and late mitochondrial damage but no cytochrome c release. This Fas ligand-induced caspase-independent death is absent in T cells that are deficient in either Fas-associated death domain (FADD) or receptor-interacting protein (RIP). RIP is also required for necrotic death induced by tumor necrosis factor (TNF) and TNF-related apoptosis-inducing ligand (TRAIL). In contrast to its role in nuclear factor kappa B activation, RIP requires its own kinase activity for death signaling. Thus, Fas, TRAIL and TNF receptors can initiate cell death by two alternative pathways, one relying on caspase-8 and the other dependent on the kinase RIP.

MeSH terms

  • Adaptor Proteins, Signal Transducing*
  • Animals
  • Apoptosis / physiology
  • Apoptosis Regulatory Proteins
  • Carrier Proteins / metabolism
  • Caspase 8
  • Caspase 9
  • Caspases / metabolism*
  • Cell Death / physiology*
  • Fas Ligand Protein
  • Fas-Associated Death Domain Protein
  • Humans
  • In Vitro Techniques
  • Jurkat Cells
  • Membrane Glycoproteins / metabolism
  • Mice
  • Mice, Inbred BALB C
  • Models, Biological
  • Necrosis
  • Proteins / metabolism*
  • Receptor-Interacting Protein Serine-Threonine Kinases
  • Signal Transduction
  • T-Lymphocytes / cytology
  • T-Lymphocytes / metabolism
  • TNF-Related Apoptosis-Inducing Ligand
  • Tumor Necrosis Factor-alpha / metabolism
  • fas Receptor / metabolism*

Substances

  • Adaptor Proteins, Signal Transducing
  • Apoptosis Regulatory Proteins
  • Carrier Proteins
  • FADD protein, human
  • FASLG protein, human
  • Fadd protein, mouse
  • Fas Ligand Protein
  • Fas-Associated Death Domain Protein
  • Fasl protein, mouse
  • Membrane Glycoproteins
  • Proteins
  • TNF-Related Apoptosis-Inducing Ligand
  • TNFSF10 protein, human
  • Tnfsf10 protein, mouse
  • Tumor Necrosis Factor-alpha
  • fas Receptor
  • RIPK1 protein, human
  • Receptor-Interacting Protein Serine-Threonine Kinases
  • Ripk1 protein, mouse
  • CASP8 protein, human
  • CASP9 protein, human
  • Casp8 protein, mouse
  • Casp9 protein, mouse
  • Caspase 8
  • Caspase 9
  • Caspases