Tumor necrosis factor (TNF)-like weak inducer of apoptosis (TWEAK) is a member of the TNF superfamily that has been shown to induce angiogenesis, apoptosis in tumor cells, and NF-κB activation through binding to its receptor fibroblast growth factor-inducible 14. We have identified TWEAK as an inducer of constitutive NF-κB activation by expression cloning, and we report here sequential regulation by TWEAK of two separate signaling caseades for NF-κB activation, the NF-κB essential modulator-dependent and -independent signaling pathways. Upon TWEAK stimulation, IκB is rapidly phosphorylated, generating NF-κB DNA-binding complexes containing p50 and RelA in a manner dependent on the canonical IκB kinase complex. Unlike TNF-α, TWEAK stimulation results in prolonged NF-κB activation with a transition of the DNA-binding NF-κB components from RelA- to RelB-containing complexes by 8 h, and the latter remained active in binding at least until 24 h post-stimulation. This long lasting activation is accompanied by the proteasome-mediated processing of NF-κB2/p100, which does not depend on the NF-κB essential modulator but requires IκB kinase 1 and functional NF-κB-inducing kinase activity. Finally, we show that fibroblast growth factor-inducible 14 with a mutation at its TNF receptor-associated factor (TRAF)-binding site cannot activate NF-κB and that TWEAK fails to induce the p100 processing and IκBα phosphorylation in cells deficient for TRAF2 and TRAF5. Our results thus identify TWEAK as a novel physiological regulator of the non-canonical pathway for NF-κB activation.
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