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

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).
Mesh Terms:
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
Cell
Date: Feb. 10, 2006
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