Department of Biochemistry, University of Cambridge, 80 Tennis Court Road, Cambridge, CB2 1GA, UK.
Institute of Bioengineering, School of Life Sciences, Ecole Polytechnique Fédérale de Lausanne, Lausanne, Switzerland.
Nat Commun. 2022 Aug 30;13(1):5110. doi: 10.1038/s41467-022-32690-6.
Aedes aegypti has evolved to become an efficient vector for arboviruses but the mechanisms of host-pathogen tolerance are unknown. Immunoreceptor Toll and its ligand Spaetzle have undergone duplication which may allow neofunctionalization and adaptation. Here we present cryo-EM structures and biophysical characterisation of low affinity Toll5A complexes that display transient but specific interactions with Spaetzle1C, forming asymmetric complexes, with only one ligand clearly resolved. Loop structures of Spaetzle1C and Toll5A intercalate, temporarily bridging the receptor C-termini to promote signalling. By contrast unbound receptors form head-to-head homodimers that keep the juxtamembrane regions far apart in an inactive conformation. Interestingly the transcriptional signature of Spaetzle1C differs from other Spaetzle cytokines and controls genes involved in innate immunity, metabolism and tissue regeneration. Taken together our results explain how upregulation of Spaetzle1C in the midgut and Toll5A in the salivary gland shape the concomitant immune response.
埃及伊蚊已进化为一种高效的虫媒病毒载体，但宿主-病原体耐受的机制尚不清楚。免疫受体 Toll 及其配体 Spaetzle 经历了复制，这可能允许新功能化和适应。在这里，我们展示了低亲和力 Toll5A 复合物的冷冻电镜结构和生物物理特性，这些复合物与 Spaetzle1C 显示出短暂但特异性的相互作用，形成不对称复合物，只有一个配体清晰可辨。Spaetzle1C 和 Toll5A 的环结构相互穿插，暂时桥接受体 C 端以促进信号转导。相比之下，未结合的受体形成头对头的同源二聚体，使靠近膜区域在非活性构象中保持很远的距离。有趣的是，Spaetzle1C 的转录特征与其他 Spaetzle 细胞因子不同，它控制参与先天免疫、代谢和组织再生的基因。总之，我们的研究结果解释了为什么中肠中 Spaetzle1C 的上调和唾液腺中 Toll5A 的上调会塑造伴随的免疫反应。
