The E3 Ubiquitin Ligase Itch Couples JNK Activation to TNFalpha-induced Cell Death by Inducing c-FLIP(L) Turnover

Cell. 2006 Feb 10;124(3):601-13. doi: 10.1016/j.cell.2006.01.021.

Abstract

The proinflammatory cytokine tumor necrosis factor (TNF) alpha signals both cell survival and death. The biological outcome of TNFalpha treatment is determined by the balance between NF-kappaB and Jun kinase (JNK) signaling; NF-kappaB promotes survival, whereas JNK enhances cell death. Critically, identity of a JNK substrate that promotes TNFalpha-induced apoptosis has been outstanding. Here we show that TNFalpha-mediated JNK activation accelerates turnover of the NF-kappaB-induced antiapoptotic protein c-FLIP, an inhibitor of caspase-8. This is not due to direct c-FLIP phosphorylation but depends on JNK-mediated phosphorylation and activation of the E3 ubiquitin ligase Itch, which specifically ubiquitinates c-FLIP and induces its proteasomal degradation. JNK1 or Itch deficiency or treatment with a JNK inhibitor renders mice resistant in three distinct models of TNFalpha-induced acute liver failure, and cells from these mice do not display inducible c-FLIP(L) ubiquitination and degradation. Thus, JNK antagonizes NF-kappaB during TNFalpha signaling by promoting the proteasomal elimination of c-FLIP(L).

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Apoptosis / drug effects
  • CASP8 and FADD-Like Apoptosis Regulating Protein
  • Enzyme Activation
  • Female
  • Hepatocytes / cytology
  • Hepatocytes / drug effects
  • Hepatocytes / metabolism
  • Intracellular Signaling Peptides and Proteins / metabolism*
  • JNK Mitogen-Activated Protein Kinases / metabolism*
  • Liver Failure, Acute / etiology
  • Liver Failure, Acute / metabolism
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mice, Mutant Strains
  • Models, Biological
  • Pregnancy
  • Receptors, Tumor Necrosis Factor / metabolism
  • Receptors, Tumor Necrosis Factor, Type I
  • Signal Transduction
  • Tumor Necrosis Factor Decoy Receptors
  • Tumor Necrosis Factor-alpha / pharmacology*
  • Ubiquitin-Protein Ligases / metabolism*

Substances

  • CASP8 and FADD-Like Apoptosis Regulating Protein
  • Cflar protein, mouse
  • Intracellular Signaling Peptides and Proteins
  • Receptors, Tumor Necrosis Factor
  • Receptors, Tumor Necrosis Factor, Type I
  • Tumor Necrosis Factor Decoy Receptors
  • Tumor Necrosis Factor-alpha
  • recombinant human tumor necrosis factor-binding protein-1
  • Itch protein, mouse
  • Ubiquitin-Protein Ligases
  • JNK Mitogen-Activated Protein Kinases