cIAPs Block Ripoptosome Formation, a RIP1/caspase-8 Containing Intracellular Cell Death Complex Differentially Regulated by cFLIP Isoforms

Mol Cell. 2011 Aug 5;43(3):449-63. doi: 10.1016/j.molcel.2011.06.011. Epub 2011 Jul 7.

Abstract

The intracellular regulation of cell death pathways by cIAPs has been enigmatic. Here we show that loss of cIAPs promotes the spontaneous formation of an intracellular platform that activates either apoptosis or necroptosis. This 2 MDa intracellular complex that we designate "Ripoptosome" is necessary but not sufficient for cell death. It contains RIP1, FADD, caspase-8, caspase-10, and caspase inhibitor cFLIP isoforms. cFLIP(L) prevents Ripoptosome formation, whereas, intriguingly, cFLIP(S) promotes Ripoptosome assembly. When cIAPs are absent, caspase activity is the "rheostat" that is controlled by cFLIP isoforms in the Ripoptosome and decides if cell death occurs by RIP3-dependent necroptosis or caspase-dependent apoptosis. RIP1 is the core component of the complex. As exemplified by our studies for TLR3 activation, our data argue that the Ripoptosome critically influences the outcome of membrane-bound receptor triggering. The differential quality of cell death mediated by the Ripoptosome may cause important pathophysiological consequences during inflammatory responses.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Apoptosis / physiology*
  • CASP8 and FADD-Like Apoptosis Regulating Protein / metabolism
  • CASP8 and FADD-Like Apoptosis Regulating Protein / physiology*
  • Caspase 8 / metabolism
  • Caspase 8 / physiology*
  • Cell Line, Tumor
  • Humans
  • Inhibitor of Apoptosis Proteins / physiology*
  • Nuclear Pore Complex Proteins / metabolism
  • Nuclear Pore Complex Proteins / physiology*
  • Protein Isoforms / physiology
  • RNA-Binding Proteins / metabolism
  • RNA-Binding Proteins / physiology*
  • Receptors, Tumor Necrosis Factor, Type I / metabolism
  • Signal Transduction
  • Toll-Like Receptor 3 / metabolism
  • Toll-Like Receptor 3 / physiology
  • Tumor Necrosis Factor-alpha / metabolism

Substances

  • AGFG1 protein, human
  • CASP8 and FADD-Like Apoptosis Regulating Protein
  • Inhibitor of Apoptosis Proteins
  • Nuclear Pore Complex Proteins
  • Protein Isoforms
  • RNA-Binding Proteins
  • Receptors, Tumor Necrosis Factor, Type I
  • TLR3 protein, human
  • TNF protein, human
  • Toll-Like Receptor 3
  • Tumor Necrosis Factor-alpha
  • CASP8 protein, human
  • Caspase 8