Sezgin Erdinc, Azbazdar Yagmur, Ng Xue W, Teh Cathleen, Simons Kai, Weidinger Gilbert, Wohland Thorsten, Eggeling Christian, Ozhan Gunes
MRC Human Immunology Unit, Weatherall Institute of Molecular Medicine, University of Oxford, UK.
Izmir International Biomedicine and Genome Institute (iBG-izmir), Dokuz Eylul University, Izmir, Turkey.
FEBS J. 2017 Aug;284(15):2513-2526. doi: 10.1111/febs.14139. Epub 2017 Jul 6.
While the cytosolic events of Wnt/β-catenin signaling (canonical Wnt signaling) pathway have been widely studied, only little is known about the molecular mechanisms involved in Wnt binding to its receptors at the plasma membrane. Here, we reveal the influence of the immediate plasma membrane environment on the canonical Wnt-receptor interaction. While the receptors are distributed both in ordered and disordered environments, Wnt binding to its receptors selectively occurs in more ordered membrane environments which appear to cointernalize with the Wnt-receptor complex. Moreover, Wnt/β-catenin signaling is significantly reduced when the membrane order is disturbed by specific inhibitors of certain lipids that prefer to localize at the ordered environments. Similarly, a reduction in Wnt signaling activity is observed in Niemann-Pick Type C disease cells where trafficking of ordered membrane lipid components to the plasma membrane is genetically impaired. We thus conclude that ordered plasma membrane environments are essential for binding of canonical Wnts to their receptor complexes and downstream signaling activity.
虽然Wnt/β-连环蛋白信号通路（经典Wnt信号通路）的胞质事件已得到广泛研究，但对于Wnt在质膜上与其受体结合所涉及的分子机制却知之甚少。在此，我们揭示了紧邻质膜的环境对经典Wnt-受体相互作用的影响。虽然受体分布于有序和无序环境中，但Wnt与其受体的结合选择性地发生在更有序的膜环境中，这些环境似乎与Wnt-受体复合物共同内化。此外，当膜的有序性被某些倾向于定位于有序环境的特定脂质抑制剂扰乱时，Wnt/β-连环蛋白信号会显著降低。同样，在尼曼-匹克C型病细胞中观察到Wnt信号活性降低，在这些细胞中，有序膜脂成分向质膜的运输存在基因缺陷。因此，我们得出结论，有序的质膜环境对于经典Wnt与其受体复合物的结合及下游信号活性至关重要。
