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

机译:通过受体IFNAR1介导的独特干扰素-β信号转导轴的结构基础

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摘要

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.
机译:I型干扰素在调节对病原体和肿瘤的免疫反应中很重要。尽管所有干扰素的分子基础尚不清楚,但所有干扰素均被认为是通过异二聚体IFNAR1-IFNAR2复合物发出信号,但某些亚型(如干扰素-β(IFN-β))仍具有独特的功能特性。在这里,我们证明了IFN-β可以以与IFNAR2无关的方式独特地和特异性地与IFNAR1连接,并且我们提供了IFNAR1-IFN-β相互作用的结构基础。 IFNAR1-IFN-β复合物转导的信号独立于Jak-STAT通路而调节一组不同基因的表达。脂多糖诱导的败血症在Ifnar1-/-小鼠中得到改善,但在Ifnar2-/-小鼠中没有得到改善,这表明IFNAR1-IFN-β信号在病理上是相关的。因此,我们为理解IFN-β的特定功能提供了分子基础。

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