TNF-alpha induces two distinct caspase-8 activation pathways

Cell. 2008 May 16;133(4):693-703. doi: 10.1016/j.cell.2008.03.036.

Abstract

The inflammatory response of mammalian cells to TNF-alpha can be switched to apoptosis either by cotreatment with a protein synthesis inhibitor, cycloheximide, or Smac mimetic, a small molecule mimic of Smac/Diablo protein. Cycloheximide promotes caspase-8 activation by eliminating endogenous caspase-8 inhibitor, c-FLIP, while Smac mimetic does so by triggering autodegradation of cIAP1 and cIAP2 (cIAP1/2), leading to the release of receptor interacting protein kinase (RIPK1) from the activated TNF receptor complex to form a caspase-8-activating complex consisting of RIPK1, FADD, and caspase-8. This process also requires the action of CYLD, a RIPK1 K63 deubiquitinating enzyme. RIPK1 is critical for caspase-8 activation-induced by Smac mimetic but dispensable for that triggered by cycloheximide. Moreover, Smac mimetic-induced caspase-8 activation is not blocked by endogenous c-FLIP. These findings revealed that TNF-alpha is able to induce apoptosis via two distinct caspase-8 activation pathways that are differentially regulated by cIAP1/2 and c-FLIP.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Apoptosis Regulatory Proteins
  • Apoptosis*
  • Caspase 8 / metabolism*
  • Cell Line, Tumor
  • Cell Survival
  • Cycloheximide / pharmacology
  • Enzyme Activation / drug effects
  • Fas-Associated Death Domain Protein / metabolism
  • Humans
  • Inhibitor of Apoptosis Proteins / metabolism
  • Intracellular Signaling Peptides and Proteins / metabolism
  • Mitochondrial Proteins / metabolism
  • Molecular Mimicry
  • Multiprotein Complexes / metabolism
  • NF-kappa B p50 Subunit / metabolism
  • Protein Synthesis Inhibitors / pharmacology
  • Receptor-Interacting Protein Serine-Threonine Kinases / metabolism
  • Signal Transduction
  • Tumor Necrosis Factor-alpha / metabolism*

Substances

  • Apoptosis Regulatory Proteins
  • DIABLO protein, human
  • FADD protein, human
  • Fas-Associated Death Domain Protein
  • Inhibitor of Apoptosis Proteins
  • Intracellular Signaling Peptides and Proteins
  • Mitochondrial Proteins
  • Multiprotein Complexes
  • NF-kappa B p50 Subunit
  • NFKB1 protein, human
  • Protein Synthesis Inhibitors
  • TNF protein, human
  • Tumor Necrosis Factor-alpha
  • Cycloheximide
  • RIPK1 protein, human
  • Receptor-Interacting Protein Serine-Threonine Kinases
  • CASP8 protein, human
  • Caspase 8