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.

中文翻译：

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颅缝早闭相关白细胞介素 11 受体变体 p.T306_S308dup 和 p.E364_V368del 的分子特征

白细胞介素-11 (IL-11) 是细胞因子 IL-6 家族的成员，是骨稳态的重要因素。 IL-11 与膜结合 IL-11 受体（IL-11R，经典信号传导）或可溶形式的 IL-11R（sIL-11R，反式信号传导）结合并通过其发出信号。编码 IL-11R 的IL11RA基因突变与颅缝早闭有关，颅缝早闭是一种人类疾病，其中一条或多条缝线过早闭合，导致颅骨畸形。 IL-11R 内的突变如何与颅缝早闭相关的生物学机制大多尚未被探索。在这项研究中，我们分析了颅缝早闭患者中描述的 IL-11R 的两种变体：p.T306_S308dup，其导致膜近端纤连蛋白 III 型结构域内三个氨基酸残基的重复，以及 p.E364_V368del，其导致在邻近质膜的所谓茎区域中删除了五个氨基酸残基。茎区域将三个胞外结构域连接到 IL-11R 的跨膜和胞内区域，并包含产生 sIL-11R 变体的不同蛋白酶的切割位点。结合生物信息学和不同的生化、分子和细胞生物学方法，我们发现 IL-11R-T306_S308dup 变体不能正确成熟，被保留在细胞内，并且不会到达细胞表面。相比之下，IL-11R-E364_V368del 变体具有完全的生物活性，并由蛋白酶正常加工，从而允许 IL-11 的经典和反式信号传导。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，并表明其他调节机制也参与其中，但仍有待确定。