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Structural basis of a unique interferon-β signaling axis mediated via the receptor IFNAR1

Abstract

Type I interferons are important in regulating immune responses to pathogens and tumors. All interferons are considered to signal via the heterodimeric IFNAR1-IFNAR2 complex, yet some subtypes such as interferon-β (IFN-β) can exhibit distinct functional properties, although the molecular basis of this is unclear. Here we demonstrate IFN-β can uniquely and specifically ligate to IFNAR1 in an IFNAR2-independent manner, and we provide the structural basis of the IFNAR1–IFN-β interaction. The IFNAR1–IFN-β complex transduced signals that modulated expression of a distinct set of genes independently of Jak-STAT pathways. Lipopolysaccharide-induced sepsis was ameliorated in Ifnar1−/− mice but not Ifnar2−/− mice, suggesting that IFNAR1–IFN-β signaling is pathologically relevant. Thus, we provide a molecular basis for understanding specific functions of IFN-β.

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Figure 1: Interaction of IFNAR1 with IFN-β.
Figure 2: Structure of the IFNAR1–IFN-β complex.
Figure 3: Contacts between IFNAR1 and IFN-β.
Figure 4: IFNAR1 signaling in response to IFN-β in Ifnar2−/− mice.
Figure 5: Pathophysiological relevance of the IFNAR1–IFN-β signaling axis.

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Protein Data Bank

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Acknowledgements

We thank R. Smith and R. Hartmann for helpful discussions and the staff at the MX1 and MX2 beamlines at the Australian synchrotron for assistance with data collection. The Endoglycosidase H clone was a gift from K.C. Garcia (Stanford University). This work is supported by funding from the National Health and Medical Research Council (NHMRC), The Australian Research Council (ARC), the Victorian Government's Operational Infrastructure Support Program and the ARC Centre for Excellence in Structural and Functional Microbial Genomics. J.P.V. is supported by an ARC Discovery Early Career Researcher Award fellowship. N.E.M. is supported by an ARC fellowship and NHMRC. T.B. is supported by a Pfizer Australia Research Fellowship. P.J.H. is supported by an NHMRC Senior Principal Research fellowship, J.R. is supported by an NHMRC Australia Fellowship.

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N.A.d.W. carried out experiments, analyzed data, contributed to preparing the manuscript; J.P.V. solved the structure and contributed to writing the manuscript; T.K.N. and L.Z.-T. purified proteins; N.E.M. carried out in vivo mouse experiments and flow cytometry; S.-J.B. carried out in vivo LPS experiments; J.A.G. carried out microarray data and analysis; K.Y.F. carried out qRT-PCR; S.C.F. carried out microarray, promoter and transcription factor analysis; T.B. carried out SPR experiments and analysis; H.H.R. carried out protein expression and purification; and J.R. and P.J.H. led the investigation, devised the project, analyzed the data and wrote the manuscript together.

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Correspondence to Jamie Rossjohn or Paul J Hertzog.

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Data in this manuscript are the subject of Australian provisional patent application 2013902549.

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de Weerd, N., Vivian, J., Nguyen, T. et al. Structural basis of a unique interferon-β signaling axis mediated via the receptor IFNAR1. Nat Immunol 14, 901–907 (2013). https://doi.org/10.1038/ni.2667

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