Institute of Biochemistry, Kiel University, Kiel, Germany.
Institute of Psychology, Kiel University, Kiel, Germany.
Cell Rep. 2018 Oct 2;25(1):10-18.e5. doi: 10.1016/j.celrep.2018.09.005.
Premature closure of the sutures that connect the cranial bones during development of the mammalian skull results in a phenotype called craniosynostosis. Recently, several craniosynostosis patients with missense mutations within the gene encoding the interleukin-11 receptor (IL-11R) have been described, but the underlying molecular mechanisms have remained elusive. IL-11 is a cytokine that has a crucial role in bone remodeling and activates cells via binding to the IL-11R. Here, we show that patient mutations prevented maturation of the IL-11R, resulting in endoplasmic reticulum retention and diminished cell surface appearance. Disruption of a conserved tryptophan-arginine zipper within the third domain of the IL-11R was the underlying cause of the defective maturation. IL-11 classic signaling via the membrane-bound receptor, but not IL-11 trans-signaling via the soluble receptor, was the crucial pathway for normal skull development in mice in vivo. Thus, the specific therapeutic inhibition of IL-11 trans-signaling does not interfere with skull development.
哺乳动物颅骨发育过程中，颅骨之间连接的缝线过早闭合会导致颅缝早闭的表型。最近，已经描述了一些具有编码白细胞介素-11 受体（IL-11R）基因错义突变的颅缝早闭患者，但潜在的分子机制仍不清楚。IL-11 是一种细胞因子，在骨重塑中起关键作用，并通过与 IL-11R 结合来激活细胞。在这里，我们表明患者突变阻止了 IL-11R 的成熟，导致内质网滞留和细胞表面出现减少。IL-11R 第三结构域内保守的色氨酸-精氨酸拉链的破坏是成熟缺陷的根本原因。IL-11 通过膜结合受体的经典信号转导，而不是通过可溶性受体的 IL-11 转信号转导，是体内正常小鼠颅骨发育的关键途径。因此，特异性抑制 IL-11 转信号转导不会干扰颅骨发育。
