Editors' ChoiceInterferon Signaling

Different Binding Properties, Different Responses

Sci. Signal.  03 Sep 2013:
Vol. 6, Issue 291, pp. ec209
DOI: 10.1126/scisignal.2004691

Members of the family of type I interferons (IFNs), which includes multiple subtypes of IFN-α and a single IFN-β isoform, are cytokines that mediate immune responses to viruses and tumors (see commentary by Kaur and Platanias). Type I IFNs are thought to signal through the same receptor (IFNAR), a heterodimer of the high-affinity IFNAR2 subunit, which is the first subunit bound by ligand, and a low-affinity IFNAR1 subunit, which completes the ternary complex. Activation of IFNAR leads to Janus kinase (JAK)–signal transducer and activator of transcription (STAT) signaling and regulation of the expression of target genes; however, evidence suggests that IFN-β stimulates responses distinct from those of other type I IFNs. de Weerd et al. compared the binding of recombinant mouse IFN-α and IFN-β proteins to extracellular domains (ECDs) of each of the IFNAR subunits and found that IFN-β bound to IFNAR1 with an affinity 100-fold greater than that of IFN-α. The authors solved the crystal structure of IFN-β bound to the IFNAR1 ECD and found that the angle of binding of IFN-β to the receptor was different from that of other type I IFNs and that the binding interface of IFN-β with the receptor was larger than that of IFN-α2. Binding of IFN-β to IFNAR1 in peritoneal exudate cells isolated from IFNAR2-deficient mice did not stimulate JAK-STAT signaling; however, gene expression profiling identified hundreds of genes that showed altered expression in response to IFN-β. The microbial product lipopolysaccharide (LPS) stimulates the production of IFN-β, and blocking IFNAR signaling protects mice from LPS-induced death. As expected, the authors found that IFNAR1-deficient mice were protected from death induced by a concentration of LPS that killed wild-type mice. In contrast, IFNAR2-deficient mice were as susceptible to LPS-induced death as were wild-type mice. Together, these data suggest that the binding of IFN-β to IFNAR1 in the absence of IFNAR2 underlies the distinct cellular responses elicited by this cytokine.

N. A. de Weerd, J. P. Vivian, T. K. Nguyen, N. E. Mangan, J. A. Gould, S.-J. Braniff, L. Zaker-Tabrizi, K. Y. Fung, S. C. Forster, T. Beddoe, H. H. Reid, J. Rossjohn, P. J. Hertzog, Structural basis of a unique interferon-β signaling axis mediated via the receptor IFNAR1. Nat. Immunol. 14, 901–907 (2013). [PubMed]

S. Kaur, L. C. Platanias, IFN-β-specific signaling via a unique IFNAR1 interaction. Nat. Immunol. 14, 884–885 (2013). [PubMed]