Novartis Institutes for BioMedical Research, Novartis Pharma AG, 4002 Basel, Switzerland.
Novartis Institutes for BioMedical Research, Novartis Pharma AG, 4002 Basel, Switzerland.
Immunity. 2020 Mar 17;52(3):499-512.e5. doi: 10.1016/j.immuni.2020.02.004.
Interleukin-17A (IL-17A), IL-17F, and IL-17A/F heterodimers are key cytokines of the innate and adaptive immune response. Dysregulation of the IL-17 pathway contributes to immune pathology, and it is therefore important to elucidate the molecular mechanisms that govern IL-17 recognition and signaling. The receptor IL-17RC is thought to act in concert with IL-17RA to transduce IL-17A-, IL-17F-, and IL-17A/F-mediated signals. We report the crystal structure of the extracellular domain of human IL-17RC in complex with IL-17F. In contrast to the expected model, we found that IL-17RC formed a symmetrical 2:1 complex with IL-17F, thus competing with IL-17RA for cytokine binding. Using biophysical techniques, we showed that IL-17A and IL-17A/F also form 2:1 complexes with IL-17RC, suggesting the possibility of IL-17RA-independent IL-17 signaling pathways. The crystal structure of the IL-17RC:IL-17F complex provides a structural basis for IL-17F signaling through IL-17RC, with potential therapeutic applications for respiratory allergy and inflammatory bowel diseases.
白细胞介素-17A (IL-17A)、IL-17F 和 IL-17A/F 异源二聚体是先天和适应性免疫反应的关键细胞因子。IL-17 途径的失调导致免疫病理学，因此阐明调控 IL-17 识别和信号转导的分子机制非常重要。受体 IL-17RC 被认为与 IL-17RA 协同作用，转导 IL-17A、IL-17F 和 IL-17A/F 介导的信号。我们报告了人源 IL-17RC 细胞外结构域与 IL-17F 复合物的晶体结构。与预期模型相反，我们发现 IL-17RC 与 IL-17F 形成对称的 2:1 复合物，从而与 IL-17RA 竞争细胞因子结合。通过生物物理技术，我们表明 IL-17A 和 IL-17A/F 也与 IL-17RC 形成 2:1 复合物，这表明存在 IL-17RA 非依赖性的 IL-17 信号通路的可能性。IL-17RC:IL-17F 复合物的晶体结构为 IL-17RC 通过 IL-17F 进行信号转导提供了结构基础，这可能为呼吸道过敏和炎症性肠病的治疗提供应用。
