Tumor Necrosis Factor (TNF) Receptor-associated Factor 7 Is Required for TNFα-induced Jun NH2-terminal Kinase Activation and Promotes Cell Death by Regulating Polyubiquitination and Lysosomal Degradation of c-FLIP Protein*

The pro-inflammatory 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 survival factors and Jun NH2-terminal kinase (JNK) signaling, which promotes cell death. Here, we show that TRAF7, the most recently identified member of the TNF receptor-associated factors (TRAFs) family of proteins, is essential for activation of JNK following TNF alpha stimulation. We also show that TRAF6 and TRAF7 promote unconventional polyubiquitination of the antiapoptotic protein c-FLIPL and demonstrate that degradation of c-FLIPL also occurs through a lysosomal pathway. RNA interference-mediated depletion of TRAF7 correlates with increased c-FLIPL expression level, which, in turn, results in resistance to TNF alpha cytotoxicity. Collectively, our results indicate an important role for TRAF7 in the activation of JNK following TNF alpha stimulation and clearly point to an involvement of this protein in regulating the turnover of c-FLIP and, consequently, cell death.