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

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

doi:10.1016/j.cell.2006.01.021

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.

Authors

Lufen Chang¹, Hideaki Kamata, Giovanni Solinas, Jun-Li Luo, Shin Maeda, K Venuprasad, Yun-Cai Liu, Michael Karin

Affiliation

¹ Division of Cancer Immunotherapeutics & Tumor Immunology, Beckman Research Institute at City of Hope, City of Hope National Medical Center, 1500 E. Duarte Road, KCRB 3009, Duarte, CA 91010, USA.

PMID: 16469705
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