The E3 ubiquitin ligase itch couples JNK activation to TNFα-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 in hi bitor renders mice resistant in three distinct models of TNFa-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.