From the Institute of Biochemistry, Kiel University, 24118 Kiel, Germany.
From the Institute of Biochemistry, Kiel University, 24118 Kiel, Germany
J Biol Chem. 2018 Apr 27;293(17):6398-6409. doi: 10.1074/jbc.RA118.001879. Epub 2018 Mar 9.
Interleukin (IL)-11 is a multifunctional cytokine that was traditionally recognized for its hematopoietic and anti-inflammatory functions, but has recently been shown also to be involved in tumorigenesis. IL-11 signaling is initiated by binding of the cytokine to the IL-11 receptor (IL-11R), which is not directly involved in signaling but required for IL-11 binding to the signal-transducing receptor glycoprotein (gp) 130. In classic signaling, IL-11 binds to the membrane-bound IL-11R to initiate signal transduction. Additionally, IL-11 signaling can be initiated via soluble IL-11R, known as trans-signaling, and this pathway only requires the three extracellular domains of the IL-11R, but not stalk, transmembrane, or intracellular region. Here, we analyzed the role of the IL-11R stalk region, a 55 amino acid stretch connecting the extracellular domains with the transmembrane helix, in classic IL-11 signaling with the help of cytokine-dependent cell lines. We showed that the stalk region is crucial for IL-11 signaling via the membrane-bound IL-11R. Using different deletion variants, we found that a minimal length of 23 amino acid residues is required for efficient signal transduction. We further found that classic IL-11 signaling depended solely on the length, but not the sequence, of the IL-11R stalk region, suggesting that the stalk functions as a spacer in the signaling complex. We previously described the IL-11R stalk region as determinant of proteolysis and regulator of IL-11 trans-signaling. The results presented here reveal an additional function in classic IL-11 signaling, highlighting the importance of the IL-11R stalk in IL-11 signaling.
白细胞介素 (IL)-11 是一种多功能细胞因子，传统上被认为具有造血和抗炎功能，但最近也被证明参与了肿瘤发生。IL-11 信号的启动是通过细胞因子与白细胞介素-11 受体 (IL-11R) 的结合，IL-11R 本身不直接参与信号转导，但需要其与信号转导糖蛋白 (gp)130 结合。在经典信号转导中，IL-11 与膜结合的 IL-11R 结合以启动信号转导。此外，IL-11 信号还可以通过可溶性 IL-11R 启动，称为转信号，该途径仅需要 IL-11R 的三个细胞外结构域，而不需要柄、跨膜和细胞内区。在这里，我们使用依赖细胞因子的细胞系分析了 IL-11R 柄区的作用，IL-11R 柄区是连接细胞外结构域与跨膜螺旋的 55 个氨基酸延伸区。我们表明，柄区对于通过膜结合的 IL-11R 进行 IL-11 信号转导至关重要。使用不同的缺失变体，我们发现有效信号转导需要至少 23 个氨基酸残基的最小长度。我们进一步发现，经典的 IL-11 信号仅取决于 IL-11R 柄区的长度，而不取决于其序列，这表明柄区在信号复合物中充当间隔物。我们之前将 IL-11R 柄区描述为蛋白水解的决定因素和 IL-11 转信号的调节剂。这里呈现的结果揭示了经典 IL-11 信号中的另一个功能，突出了 IL-11R 柄在 IL-11 信号中的重要性。
