Department of Life Sciences, Sir Ernst Chain Building, Imperial College London, London, UK.
Division of Cell Signaling and Immunology, School of Life Sciences, University of Dundee, Dundee, UK.
EMBO Rep. 2022 Oct 6;23(10):e55450. doi: 10.15252/embr.202255450. Epub 2022 Aug 3.
Interleukin 27 (IL-27) is a heterodimeric cytokine that elicits potent immunosuppressive responses. Comprised of EBI3 and p28 subunits, IL-27 binds GP130 and IL-27Rα receptor chains to activate the JAK/STAT signaling cascade. However, how these receptors recognize IL-27 and form a complex capable of phosphorylating JAK proteins remains unclear. Here, we used cryo electron microscopy (cryoEM) and AlphaFold modeling to solve the structure of the IL-27 receptor recognition complex. Our data show how IL-27 serves as a bridge connecting IL-27Rα (domains 1-2) with GP130 (domains 1-3) to initiate signaling. While both receptors contact the p28 component of the heterodimeric cytokine, EBI3 stabilizes the complex by binding a positively charged surface of IL-27Rα and Domain 1 of GP130. We find that assembly of the IL-27 receptor recognition complex is distinct from both IL-12 and IL-6 cytokine families and provides a mechanistic blueprint for tuning IL-27 pleiotropic actions.
白细胞介素 27（IL-27）是一种异源二聚体细胞因子，可引发强烈的免疫抑制反应。由 EBI3 和 p28 亚基组成，IL-27 与 GP130 和 IL-27Rα 受体链结合，激活 JAK/STAT 信号级联。然而，这些受体如何识别 IL-27 并形成能够磷酸化 JAK 蛋白的复合物尚不清楚。在这里，我们使用冷冻电镜（cryoEM）和 AlphaFold 建模来解决 IL-27 受体识别复合物的结构。我们的数据显示了 IL-27 如何作为桥梁将 IL-27Rα（结构域 1-2）与 GP130（结构域 1-3）连接起来以启动信号转导。虽然两个受体都与异源二聚体细胞因子的 p28 成分接触，但 EBI3 通过结合 IL-27Rα 的带正电荷表面和 GP130 的结构域 1 来稳定复合物。我们发现，IL-27 受体识别复合物的组装与 IL-12 和 IL-6 细胞因子家族都不同，为调节 IL-27 的多效性作用提供了一种机制蓝图。
