Department of Pathology, Medical Faculty, Otto-von-Guericke-University Magdeburg, Germany.
Institute of Molecular Pharmacology, RWTH Aachen University, Germany.
FEBS J. 2024 Apr;291(8):1667-1683. doi: 10.1111/febs.17015. Epub 2023 Dec 7.
Interleukin-11 (IL-11) is a member of the IL-6 family of cytokines and is an important factor for bone homeostasis. IL-11 binds to and signals via the membrane-bound IL-11 receptor (IL-11R, classic signaling) or soluble forms of the IL-11R (sIL-11R, trans-signaling). Mutations in the IL11RA gene, which encodes the IL-11R, are associated with craniosynostosis, a human condition in which one or several of the sutures close prematurely, resulting in malformation of the skull. The biological mechanisms of how mutations within the IL-11R are linked to craniosynostosis are mostly unexplored. In this study, we analyze two variants of the IL-11R described in craniosynostosis patients: p.T306_S308dup, which results in a duplication of three amino-acid residues within the membrane-proximal fibronectin type III domain, and p.E364_V368del, which results in a deletion of five amino-acid residues in the so-called stalk region adjacent to the plasma membrane. The stalk region connects the three extracellular domains to the transmembrane and intracellular region of the IL-11R and contains cleavage sites for different proteases that generate sIL-11R variants. Using a combination of bioinformatics and different biochemical, molecular, and cell biology methods, we show that the IL-11R-T306_S308dup variant does not mature correctly, is intracellularly retained, and does not reach the cell surface. In contrast, the IL-11R-E364_V368del variant is fully biologically active and processed normally by proteases, thus allowing classic and trans-signaling of IL-11. Our results provide evidence that mutations within the IL11RA gene may not be causative for craniosynostosis and suggest that other regulatory mechanism(s) are involved but remain to be identified.
白细胞介素 11（IL-11）是白细胞介素 6 家族细胞因子的一员，是骨稳态的重要因素。IL-11 通过膜结合的白细胞介素 11 受体（IL-11R，经典信号）或白细胞介素 11R 的可溶性形式（sIL-11R，转导信号）结合并发出信号。编码 IL-11R 的 IL11RA 基因中的突变与颅缝早闭有关，这是一种人类疾病，其中一条或多条缝线过早闭合，导致颅骨畸形。IL-11R 内突变与颅缝早闭之间的生物学机制在很大程度上尚未得到探索。在这项研究中，我们分析了在颅缝早闭患者中描述的两种 IL-11R 变体：p.T306_S308dup，导致膜近端纤维连接蛋白 III 结构域内三个氨基酸残基的重复，以及 p.E364_V368del，导致紧邻质膜的所谓茎区的五个氨基酸残基缺失。茎区将三个细胞外结构域连接到 IL-11R 的跨膜和细胞内区，并包含不同蛋白酶的切割位点，这些蛋白酶生成 sIL-11R 变体。我们使用生物信息学和不同的生化、分子和细胞生物学方法的组合，表明 IL-11R-T306_S308dup 变体不能正确成熟，在细胞内保留，并且不能到达细胞表面。相比之下，IL-11R-E364_V368del 变体是完全生物活性的，并且被蛋白酶正常加工，从而允许 IL-11 的经典和转导信号。我们的结果提供了证据，表明 IL11RA 基因内的突变可能不是颅缝早闭的原因，并表明涉及其他调节机制，但仍有待确定。
