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

Abstract

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-κB (nuclear factor kappa B) transcription factors. Previous studies established that IFNα/β activates NF-κB to promote cell survival through a phosphatidylinositol 3-kinase (PI3K)/ Akt pathway, which involves serine phosphorylation and degradation of Iκbα. We now describe a second pathway by which IFNs activate NF-κB that is independent of IκB degradation. This pathway involves NF-κB-inducing kinase (NIK) and the tumor necrosis factor receptor-associated factor-2 (TKAF2) and results in IFNα/β-induced processing of the p100/NF-κB2 precursor into p52. IFNα/β stimulates NF-κB DNA binding and NF-κB-dependent transcription. Whereas expression of NIK and TRAF2 constructs causes NF-κB activation, expression of dominant negative NIK and TRAF2 constructs blocks IFN-promoted NF-κB activation and IFN-stimulated κB-dependent transcription and IFNα/β-induced processing of the p100/NF-κB2 precursor into p52. In contrast, PI3K does not mediate IFNα/β-induced p100 processing, although PI3K is involved in the pathway resulting in IκBα 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 TBAF2, previously shown to function in TNF signaling, within the IFN signal transduction pathway. Thus, IFN induces NF-κB activation to mediate IFN-dependent cell survival signals through a "canonical" pathway of IκBα proteolysis mediated by PI3K/Akt and a "noncanonical" pathway of p100 processing mediated by NIK/TRAF. © 2005 by The American Society for Biochemistry and Molecular Biology, Inc.