The role of TRAF2 binding to the type I interferon receptor in alternative NF kappaB activation and antiviral response.
Type I interferons (IFNs) play critical roles in the host defense by modulating gene expression through the IFN-dependent activation of STAT and NFkappaB transcription factors. Previous studies established that IFN activates NFkappaB through a classical NFkappaB pathway that results in IkappaBalpha degradation and formation of p50-containing NFkappaB complexes, as well as an alternative pathway that involves NFkappaB-inducing kinase and TRAF2, which results in the formation of p52-containing NFkappaB 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 NFkappaB pathway by IFN, but not the classical NFkappaB 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.
Yang
Chuan He
CH
Department of Pathology and Laboratory Medicine, University of Tennessee Health Science Center, and the Center for Cancer Research, Memphis, TN 38163, USA.
Murti
Aruna
A
Pfeffer
Susan R
SR
Fan
Meiyun
M
Du
Ziyun
Z
Pfeffer
Lawrence M
LM
D000818:Animals; D002460:Cell Line; D006801:Humans; D007372:Interferons / Q000494:pharmacology; D051379:Mice; D018345:Mice, Knockout; D050296:Microbial Viability; D016328:NF-kappa B / Q000378:metabolism*; D011485:Protein Binding; D051381:Rats; D053633:Receptor, Interferon alpha-beta / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D047992:TNF Receptor-Associated Factor 2 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D018116:Vesiculovirus / Q000502:physiology*
D016328:NF-kappa B; D047992:TNF Receptor-Associated Factor 2; D053633:Receptor, Interferon alpha-beta; D007372:Interferons