The E3 ubiquitin ligase itch couples JNK activation to TNFα-induced cell death by inducing c-FLIPL turnover

Lufen Chang, Hideaki Kamata, Giovanni Solinas, Jun Li Luo, Shin Maeda, K. Venuprasad, Yun Cai Liu, Michael Karin

Research output: Contribution to journalArticle

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Abstract

The proinflammatory cytokine tumor necrosis factor (TNF) α signals both cell survival and death. The biological outcome of TNFα treatment is determined by the balance between NF-κB and Jun kinase (JNK) signaling; NF-κB promotes survival, whereas JNK enhances cell death. Critically, identity of a JNK substrate that promotes TNFα-induced apoptosis has been outstanding. Here we show that TNFα-mediated JNK activation accelerates turnover of the NF-κB-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 TNFα-induced acute liver failure, and cells from these mice do not display inducible c-FLIPL ubiquitination and degradation. Thus, JNK antagonizes NF-κB during TNFα signaling by promoting the proteasomal elimination of c-FLIP L.

Original languageEnglish (US)
Pages (from-to)601-613
Number of pages13
JournalCell
Volume124
Issue number3
DOIs
StatePublished - Feb 10 2006
Externally publishedYes

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Ubiquitin-Protein Ligases
Cell death
Cell Death
Phosphotransferases
Tumor Necrosis Factor-alpha
Chemical activation
Phosphorylation
CASP8 and FADD-Like Apoptosis Regulating Protein
Degradation
Acute Liver Failure
Caspase 8
Ubiquitination
Liver
Cell Survival
Cells
Apoptosis
Cytokines
Substrates

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

Cite this

The E3 ubiquitin ligase itch couples JNK activation to TNFα-induced cell death by inducing c-FLIPL turnover. / Chang, Lufen; Kamata, Hideaki; Solinas, Giovanni; Luo, Jun Li; Maeda, Shin; Venuprasad, K.; Liu, Yun Cai; Karin, Michael.

In: Cell, Vol. 124, No. 3, 10.02.2006, p. 601-613.

Research output: Contribution to journalArticle

Chang, L, Kamata, H, Solinas, G, Luo, JL, Maeda, S, Venuprasad, K, Liu, YC & Karin, M 2006, 'The E3 ubiquitin ligase itch couples JNK activation to TNFα-induced cell death by inducing c-FLIPL turnover', Cell, vol. 124, no. 3, pp. 601-613. https://doi.org/10.1016/j.cell.2006.01.021
Chang, Lufen ; Kamata, Hideaki ; Solinas, Giovanni ; Luo, Jun Li ; Maeda, Shin ; Venuprasad, K. ; Liu, Yun Cai ; Karin, Michael. / The E3 ubiquitin ligase itch couples JNK activation to TNFα-induced cell death by inducing c-FLIPL turnover. In: Cell. 2006 ; Vol. 124, No. 3. pp. 601-613.
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AU - Venuprasad, K.

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