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

Nicole Anne De Weerd, Julian Vivian, Thao K Nguyen, Niamh Mangan, Jodee Ann Gould, Susie-Jane Braniff, Leyla Zaker-Tabrizi, Ka Yee Fung, Samuel Forster, Travis Clarke Beddoe, Hugh Harrington Reid, Jamie Rossjohn, Paul John Hertzog

Research output: Contribution to journalArticleResearchpeer-review

128 Citations (Scopus)

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-beta (IFN-beta) can exhibit distinct functional properties, although the molecular basis of this is unclear. Here we demonstrate IFN-beta can uniquely and specifically ligate to IFNAR1 in an IFNAR2-independent manner, and we provide the structural basis of the IFNAR1-IFN-beta interaction. The IFNAR1-IFN-beta 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-beta signaling is pathologically relevant. Thus, we provide a molecular basis for understanding specific functions of IFN-beta.
Original languageEnglish
Pages (from-to)901 - 907
Number of pages7
JournalNature Immunology
Volume14
Issue number9
DOIs
Publication statusPublished - 2013

Cite this

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title = "Structural basis of a unique interferon-beta 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-beta (IFN-beta) can exhibit distinct functional properties, although the molecular basis of this is unclear. Here we demonstrate IFN-beta can uniquely and specifically ligate to IFNAR1 in an IFNAR2-independent manner, and we provide the structural basis of the IFNAR1-IFN-beta interaction. The IFNAR1-IFN-beta 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-beta signaling is pathologically relevant. Thus, we provide a molecular basis for understanding specific functions of IFN-beta.",
author = "{De Weerd}, {Nicole Anne} and Julian Vivian and Nguyen, {Thao K} and Niamh Mangan and Gould, {Jodee Ann} and Susie-Jane Braniff and Leyla Zaker-Tabrizi and Fung, {Ka Yee} and Samuel Forster and Beddoe, {Travis Clarke} and Reid, {Hugh Harrington} and Jamie Rossjohn and Hertzog, {Paul John}",
year = "2013",
doi = "10.1038/ni.2667",
language = "English",
volume = "14",
pages = "901 -- 907",
journal = "Nature Immunology",
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publisher = "Nature Publishing Group",
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Structural basis of a unique interferon-beta signaling axis mediated via the receptor IFNAR1. / De Weerd, Nicole Anne; Vivian, Julian; Nguyen, Thao K; Mangan, Niamh; Gould, Jodee Ann; Braniff, Susie-Jane; Zaker-Tabrizi, Leyla; Fung, Ka Yee; Forster, Samuel; Beddoe, Travis Clarke; Reid, Hugh Harrington; Rossjohn, Jamie; Hertzog, Paul John.

In: Nature Immunology, Vol. 14, No. 9, 2013, p. 901 - 907.

Research output: Contribution to journalArticleResearchpeer-review

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AU - De Weerd, Nicole Anne

AU - Vivian, Julian

AU - Nguyen, Thao K

AU - Mangan, Niamh

AU - Gould, Jodee Ann

AU - Braniff, Susie-Jane

AU - Zaker-Tabrizi, Leyla

AU - Fung, Ka Yee

AU - Forster, Samuel

AU - Beddoe, Travis Clarke

AU - Reid, Hugh Harrington

AU - Rossjohn, Jamie

AU - Hertzog, Paul John

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AB - 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-beta (IFN-beta) can exhibit distinct functional properties, although the molecular basis of this is unclear. Here we demonstrate IFN-beta can uniquely and specifically ligate to IFNAR1 in an IFNAR2-independent manner, and we provide the structural basis of the IFNAR1-IFN-beta interaction. The IFNAR1-IFN-beta 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-beta signaling is pathologically relevant. Thus, we provide a molecular basis for understanding specific functions of IFN-beta.

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