Ligand-independent interaction of the type I interferon receptor complex is necessary to observe its biological activity

Ectopic coexpression of the two chains of the Type land Type III interferon (IFN) receptor complexes (IFN-alpha R1 and IFN-alpha R2c, or IFN-lambda R1 and IL-10R2) yielded sensitivity to IFN-alpha or IFN-Iambda in only some cells. We found that IFN-alpha R1 and IFN-alpha R2c exhibit FRET only when expressed at equivalent and low levels. Expanded clonal cell lines expressing both IFN-alpha R1 and IFN-alpha R2c were sensitive to IFN-alpha only when IFN-alpha R1 and IFN-alpha R2c exhibited FRET in the absence of human IFN-alpha. Coexpression of RACK-1 or jak1 enhanced the affinity of the interaction between IFN-alpha R1 and IFN-alpha R2c. Both IFN-alpha R1 and IFN-alpha R2c exhibited FRET with Jak1 and Tyk2. Together with data showing that disruption of the pre-association between the IFN-gamma receptor chains inhibited its biological activity, we propose that biologically active IFN receptors require ligand-independent juxtaposition of IFN receptor chains assisted by their associated cytosolic proteins. (C) 2013 Elsevier Ltd. All rights reserved.