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The E3 ubiquitin ligase itch couples JNK activation to TNF alpha-induced cell death by inducing c-FLIP(L) turnover

Academic Article
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Overview

authors

  • Chang, L. F.
  • Kamata, H.
  • Solinas, G.
  • Luo, Junli
  • Maeda, S.
  • Venuprasad, K.
  • Liu, Y. C.
  • Karin, M.

publication date

  • February 2006

journal

  • Cell  Journal

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).

subject areas

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

International Standard Serial Number (ISSN)

  • 0092-8674

Digital Object Identifier (DOI)

  • 10.1016/j.cell.2006.01.021

PubMed ID

  • 16469705
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Additional Document Info

start page

  • 601

end page

  • 613

volume

  • 124

issue

  • 3

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