The E3 Ubiquitin Ligase Itch Couples JNK Activation to TNF(alpha)-induced Cell Death by Inducing c-FLIPL Turnover

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