The Ripoptosome, a Signaling Platform That Assembles in Response to Genotoxic Stress and Loss of IAPs

Mol Cell. 2011 Aug 5;43(3):432-48. doi: 10.1016/j.molcel.2011.06.006. Epub 2011 Jul 7.

Abstract

A better understanding of the mechanisms through which anticancer drugs exert their effects is essential to improve combination therapies. While studying how genotoxic stress kills cancer cells, we discovered a large ∼2MDa cell death-inducing platform, referred to as "Ripoptosome." It contains the core components RIP1, FADD, and caspase-8, and assembles in response to genotoxic stress-induced depletion of XIAP, cIAP1 and cIAP2. Importantly, it forms independently of TNF, CD95L/FASL, TRAIL, death-receptors, and mitochondrial pathways. It also forms upon Smac-mimetic (SM) treatment without involvement of autocrine TNF. Ripoptosome assembly requires RIP1's kinase activity and can stimulate caspase-8-mediated apoptosis as well as caspase-independent necrosis. It is negatively regulated by FLIP, cIAP1, cIAP2, and XIAP. Mechanistically, IAPs target components of this complex for ubiquitylation and inactivation. Moreover, we find that etoposide-stimulated Ripoptosome formation converts proinflammatory cytokines into prodeath signals. Together, our observations shed new light on fundamental mechanisms by which chemotherapeutics may kill cancer cells.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Agents / pharmacology
  • Apoptosis / drug effects
  • Apoptosis / physiology*
  • CASP8 and FADD-Like Apoptosis Regulating Protein / genetics
  • CASP8 and FADD-Like Apoptosis Regulating Protein / metabolism
  • CASP8 and FADD-Like Apoptosis Regulating Protein / physiology
  • Caspase 8 / chemistry
  • Caspase 8 / metabolism
  • Caspase 8 / physiology*
  • Cell Line, Tumor
  • DNA Damage*
  • Enzyme Activation
  • Etoposide / pharmacology
  • Fas-Associated Death Domain Protein / chemistry
  • Fas-Associated Death Domain Protein / metabolism
  • Fas-Associated Death Domain Protein / physiology*
  • Humans
  • Inhibitor of Apoptosis Proteins / genetics*
  • Inhibitor of Apoptosis Proteins / physiology
  • Ligands
  • Mitochondria / metabolism
  • Nuclear Pore Complex Proteins / chemistry
  • Nuclear Pore Complex Proteins / metabolism
  • Nuclear Pore Complex Proteins / physiology*
  • RNA-Binding Proteins / chemistry
  • RNA-Binding Proteins / metabolism
  • RNA-Binding Proteins / physiology*
  • Signal Transduction

Substances

  • AGFG1 protein, human
  • Antineoplastic Agents
  • CASP8 and FADD-Like Apoptosis Regulating Protein
  • FADD protein, human
  • Fas-Associated Death Domain Protein
  • Inhibitor of Apoptosis Proteins
  • Ligands
  • Nuclear Pore Complex Proteins
  • RNA-Binding Proteins
  • Etoposide
  • CASP8 protein, human
  • Caspase 8