The role of TRAF2 binding to the type I interferon receptor in alternative NFκB activation and antiviral response

Abstract

Type I interferons (IFNs) play critical roles in the host defense by modulating gene expression through the IFN-dependent activation of STAT and NFκB transcription factors. Previous studies established that IFN activates NFκB through a classical NFκB pathway that results in IκBα degradation and formation of p50-containing NFκB complexes, as well as an alternative pathway that involves NFκB-inducing kinase and TRAF2, which results in the formation of p52-containing NFκB complexes. In this study, we examined the interaction of TRAF proteins with the type I IFN receptor. We found that TRAF2 was directly coupled to the signal-transducing IFNAR1 subunit of the IFN receptor. By immunoprecipitation, overexpression of epitope-tagged IFNAR1 constructs, and glutathione S-transferase pulldown experiments, we demonstrate that TRAF2 rapidly binds to the IFNAR1 subunit of the IFN receptor upon IFN binding. The membrane proximal half of the IFNAR1 subunit was found to directly bind TRAF2. Moreover, analysis of mouse embryo fibroblasts derived from TRAF2 knock-out mice demonstrated that TRAF2 plays a critical role in the activation of the alternative NFκB pathway by IFN, but not the classical NFκB pathway, as well as in the antiviral action of IFN. Our results place TRAF2 directly in the signaling pathway transduced through the IFNAR1 subunit of the IFN receptor. These findings provide an important insight into the molecular mechanisms by which IFN generates signals to induce its biological effects. © 2008 by The American Society for Biochemistry and Molecular Biology, Inc.