Induction of TNF receptor I-mediated apoptosis via two sequential signaling complexes

Cell. 2003 Jul 25;114(2):181-90. doi: 10.1016/s0092-8674(03)00521-x.

Abstract

Apoptosis induced by TNF-receptor I (TNFR1) is thought to proceed via recruitment of the adaptor FADD and caspase-8 to the receptor complex. TNFR1 signaling is also known to activate the transcription factor NF-kappa B and promote survival. The mechanism by which this decision between cell death and survival is arbitrated is not clear. We report that TNFR1-induced apoptosis involves two sequential signaling complexes. The initial plasma membrane bound complex (complex I) consists of TNFR1, the adaptor TRADD, the kinase RIP1, and TRAF2 and rapidly signals activation of NF-kappa B. In a second step, TRADD and RIP1 associate with FADD and caspase-8, forming a cytoplasmic complex (complex II). When NF-kappa B is activated by complex I, complex II harbors the caspase-8 inhibitor FLIP(L) and the cell survives. Thus, TNFR1-mediated-signal transduction includes a checkpoint, resulting in cell death (via complex II) in instances where the initial signal (via complex I, NF-kappa B) fails to be activated.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing*
  • Apoptosis / physiology*
  • CASP8 and FADD-Like Apoptosis Regulating Protein
  • Carrier Proteins / metabolism
  • Caspase 8
  • Caspase 9
  • Caspase Inhibitors
  • Caspases / metabolism
  • Cell Membrane / metabolism
  • Cell Survival / physiology
  • Cytoplasm / metabolism
  • Fas-Associated Death Domain Protein
  • Humans
  • Intracellular Signaling Peptides and Proteins*
  • Jurkat Cells
  • Models, Biological
  • NF-kappa B / drug effects
  • NF-kappa B / genetics
  • NF-kappa B / metabolism
  • Nuclear Pore Complex Proteins / metabolism
  • Proteins / genetics
  • Proteins / immunology
  • Proteins / metabolism*
  • RNA-Binding Proteins*
  • Receptors, Tumor Necrosis Factor / genetics
  • Receptors, Tumor Necrosis Factor / immunology
  • Receptors, Tumor Necrosis Factor / metabolism*
  • Signal Transduction*
  • TNF Receptor-Associated Factor 1
  • Transcriptional Activation
  • Tumor Cells, Cultured
  • Tumor Necrosis Factor-alpha / metabolism
  • Tumor Necrosis Factor-alpha / pharmacology
  • fas Receptor / metabolism

Substances

  • AGFG1 protein, human
  • Adaptor Proteins, Signal Transducing
  • CASP8 and FADD-Like Apoptosis Regulating Protein
  • CFLAR protein, human
  • Carrier Proteins
  • Caspase Inhibitors
  • FADD protein, human
  • Fas-Associated Death Domain Protein
  • Intracellular Signaling Peptides and Proteins
  • NF-kappa B
  • Nuclear Pore Complex Proteins
  • Proteins
  • RNA-Binding Proteins
  • Receptors, Tumor Necrosis Factor
  • T2BP protein, human
  • TNF Receptor-Associated Factor 1
  • Tumor Necrosis Factor-alpha
  • fas Receptor
  • CASP8 protein, human
  • CASP9 protein, human
  • Caspase 8
  • Caspase 9
  • Caspases