Mendoza Juan L, Schneider William M, Hoffmann Hans-Heinrich, Vercauteren Koen, Jude Kevin M, Xiong Anming, Moraga Ignacio, Horton Tim M, Glenn Jeffrey S, de Jong Ype P, Rice Charles M, Garcia K Christopher
Howard Hughes Medical Institute, Department of Molecular and Cellular Physiology and Department of Structural Biology, Stanford University School of Medicine, Stanford, CA 94305, USA.
Laboratory of Virology and Infectious Disease, The Rockefeller University, New York, NY 10065, USA.
Immunity. 2017 Mar 21;46(3):379-392. doi: 10.1016/j.immuni.2017.02.017.
Type III interferons (IFN-λs) signal through a heterodimeric receptor complex composed of the IFN-λR1 subunit, specific for IFN-λs, and interleukin-10Rβ (IL-10Rβ), which is shared by multiple cytokines in the IL-10 superfamily. Low affinity of IL-10Rβ for cytokines has impeded efforts aimed at crystallizing cytokine-receptor complexes. We used yeast surface display to engineer a higher-affinity IFN-λ variant, H11, which enabled crystallization of the ternary complex. The structure revealed that IL-10Rβ uses a network of tyrosine residues as hydrophobic anchor points to engage IL-10 family cytokines that present complementary hydrophobic binding patches, explaining its role as both a cross-reactive but cytokine-specific receptor. H11 elicited increased anti-proliferative and antiviral activities in vitro and in vivo. In contrast, engineered higher-affinity type I IFNs did not increase antiviral potency over wild-type type I IFNs. Our findings provide insight into cytokine recognition by the IL-10R family and highlight the plasticity of type III interferon signaling and its therapeutic potential.
III型干扰素（IFN-λs）通过一种异二聚体受体复合物进行信号传导，该复合物由对IFN-λs具有特异性的IFN-λR1亚基和白细胞介素10受体β（IL-10Rβ）组成，IL-10Rβ为IL-10超家族中的多种细胞因子所共有。IL-10Rβ对细胞因子的低亲和力阻碍了细胞因子-受体复合物结晶的相关研究。我们利用酵母表面展示技术构建了一种高亲和力的IFN-λ变体H11，它能够使三元复合物结晶。该结构表明，IL-10Rβ利用酪氨酸残基网络作为疏水锚定点，与呈现互补疏水结合位点的IL-10家族细胞因子结合，这解释了其作为交叉反应但细胞因子特异性受体的作用。H11在体外和体内均引发了增强的抗增殖和抗病毒活性。相比之下，构建的高亲和力I型干扰素在抗病毒效力上并未超过野生型I型干扰素。我们的研究结果为IL-10R家族对细胞因子的识别提供了见解，并突出了III型干扰素信号传导的可塑性及其治疗潜力。
