Department of Biochemistry, University of Oxford, South Parks Road, Oxford, OX1 3QU, UK.
Kavli Institute for Nanoscience Discovery, Dorothy Crowfoot Hodgkin Building, University of Oxford, South Parks Rd, Oxford, OX1 3QU, UK.
Nat Commun. 2024 Jun 19;15(1):5226. doi: 10.1038/s41467-024-49550-0.
IL-33 plays a significant role in inflammation, allergy, and host defence against parasitic helminths. The model gastrointestinal nematode Heligmosomoides polygyrus bakeri secretes the Alarmin Release Inhibitor HpARI2, an effector protein that suppresses protective immune responses and asthma in its host by inhibiting IL-33 signalling. Here we reveal the structure of HpARI2 bound to mouse IL-33. HpARI2 contains three CCP-like domains, and we show that it contacts IL-33 primarily through the second and third of these. A large loop which emerges from CCP3 directly contacts IL-33 and structural comparison shows that this overlaps with the binding site on IL-33 for its receptor, ST2, preventing formation of a signalling complex. Truncations of HpARI2 which lack the large loop from CCP3 are not able to block IL-33-mediated signalling in a cell-based assay and in an in vivo female mouse model of asthma. This shows that direct competition between HpARI2 and ST2 is responsible for suppression of IL-33-dependent responses.
IL-33 在炎症、过敏和宿主防御寄生虫蠕虫中发挥重要作用。模式胃肠道线虫 Heligmosomoides polygyrus bakeri 分泌警报素释放抑制剂 HpARI2，这是一种效应蛋白，通过抑制 IL-33 信号通路来抑制宿主的保护性免疫反应和哮喘。在这里，我们揭示了与小鼠 IL-33 结合的 HpARI2 的结构。HpARI2 包含三个 CCP 样结构域，我们表明它主要通过其中的第二和第三个结构域与 IL-33 接触。一个从 CCP3 中出现的大环直接与 IL-33 接触，结构比较表明，这与 IL-33 与其受体 ST2 的结合位点重叠，阻止了信号复合物的形成。缺乏 CCP3 大环的 HpARI2 截断片段无法在基于细胞的测定和哮喘的雌性小鼠体内模型中阻断 IL-33 介导的信号转导。这表明 HpARI2 和 ST2 之间的直接竞争是抑制 IL-33 依赖性反应的原因。
