PDF(Pubmed)
Abstract：
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.
摘要：
IL-33在炎症中起重要作用，过敏,和宿主防御寄生虫。胃肠道线虫模型分泌Alarmin释放抑制剂HpARI2，这是一种效应蛋白，可通过抑制IL-33信号传导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，我们发现它主要通过第二和第三接触IL-33。从CCP3出现的大环直接接触IL-33，结构比较表明，这与IL-33上的受体结合位点重叠，ST2,防止信号传导复合物的形成。缺乏来自CCP3的大环的HpARI2的截短不能在基于细胞的测定和在哮喘的体内雌性小鼠模型中阻断IL-33介导的信号传导。这表明HpARI2和ST2之间的直接竞争负责抑制IL-33依赖性应答。
