Centre for Innate Immunity and Infectious Diseases, Monash Institute of Medical Research, Monash University, Clayton, Victoria, Australia.
Nat Immunol. 2013 Sep;14(9):901-7. doi: 10.1038/ni.2667. Epub 2013 Jul 21.
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.
I 型干扰素在调节病原体和肿瘤的免疫反应方面具有重要作用。所有干扰素都被认为通过异二聚体 IFNAR1-IFNAR2 复合物传递信号，但有些亚型（如干扰素-β [IFN-β]）可以表现出独特的功能特性，尽管其分子基础尚不清楚。在这里，我们证明 IFN-β 可以以 IFNAR2 独立的方式独特且特异性地与 IFNAR1 连接，并提供了 IFNAR1-IFN-β 相互作用的结构基础。IFNAR1-IFN-β 复合物转导的信号调节了一组独特基因的表达，而不依赖 Jak-STAT 途径。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 信号传递与病理相关。因此，我们为理解 IFN-β 的特定功能提供了分子基础。
