Interferon induces NF-κB-inducing kinase/tumor necrosis factor receptor-associated factor-dependent NF-κB activation to promote cell survival

Type I interferons (IFNs) play critical roles in the host defense by modulating the expression of various genes via the IFN-dependent activation of signal transducers and activators of transcription and NF-kappa B (nuclear factor kappa B) transcription factors. Previous studies established that IFN alpha/beta activates NF-kappa B to promote cell survival through a phosphatidylinositol 3-kinase (PI3K)/Akt pathway, which involves serine phosphorylation and degradation of I kappa B alpha. We now describe a second pathway by which IFNs activate NF-kappa B that is independent of I kappa B degradation. This pathway involves NF-kappa B-inducing kinase (NIK) and the tumor necrosis factor receptor-associated factor-2 (TRAF2) and results in IFN alpha/beta-induced processing of the p100/NF-kappa B2 precursor into p52. IFN alpha/beta stimulates NF-kappa B DNA binding and NF-kappa B-dependent transcription. Whereas expression of NIK and TRAF2 constructs causes NF-kappa B activation, expression of dominant negative NIK and TRAF2 constructs blocks IFN-promoted NF-kappa B activation and IFN-stimulated kappa B-dependent transcription and IFN alpha/beta-induced processing of the p100/NF-kappa B2 precursor into p52. In contrast, PI3K does not mediate IFN alpha/beta-induced p100 processing, although PI3K is involved in the pathway resulting in I kappa B alpha degradation. Moreover, whereas IFN promotes cell survival in lymphoblastoid cells, expression of dominant negative NIK and TRAF2 constructs enhances IFN-induced apoptosis. Our results for the first time place NIK and TRAF2, previously shown to function in TNF signaling, within the IFN signal transduction pathway. Thus, IFN induces NF-kappa B activation to mediate IFN-dependent cell survival signals through a canonical pathway of I kappa B alpha proteolysis mediated by PI3K/Akt and a noncanonical pathway of p100 processing mediated by NIK/TRAF.