Endothelial Cell Biology Laboratory, MRC Laboratory for Molecular Cell Biology, University College London, London, UK.
Endothelial Cell Biology Laboratory, MRC Laboratory for Molecular Cell Biology, University College London, London, UK.
Dev Cell. 2019 Jun 3;49(5):786-801.e6. doi: 10.1016/j.devcel.2019.04.006. Epub 2019 May 2.
How can anterograde membrane trafficking be modulated by physiological cues? A screen of Golgi-associated proteins revealed that the ARF-GEF GBF1 can selectively modulate the ER-Golgi trafficking of prohaemostatic von Willebrand factor (VWF) and extracellular matrix (ECM) proteins in human endothelial cells and in mouse fibroblasts. The relationship between levels of GBF1 and the trafficking of VWF into forming secretory granules confirmed GBF1 is a limiting factor in this process. Further, GBF1 activation by AMPK couples its control of anterograde trafficking to physiological cues; levels of glucose control GBF1 activation in turn modulating VWF trafficking into secretory granules. GBF1 modulates both ER and TGN exit, the latter dramatically affecting the size of the VWF storage organelles, thereby influencing the hemostatic capacity of the endothelium. The role of AMPK as a central integrating element of cellular pathways with intra- and extra-cellular cues can now be extended to modulation of the anterograde secretory pathway.
生理信号如何调节顺行膜转运？通过对高尔基相关蛋白的筛选发现，ARF-GEF GBF1 可以选择性地调节人内皮细胞和小鼠成纤维细胞中促凝止血 von Willebrand 因子 (VWF) 和细胞外基质 (ECM) 蛋白的 ER-Golgi 转运。GBF1 水平与 VWF 进入形成分泌颗粒的转运之间的关系证实了 GBF1 是该过程的限制因素。此外，AMPK 对 GBF1 的激活将其对顺行转运的控制与生理信号联系起来；葡萄糖水平控制 GBF1 的激活，从而调节 VWF 进入分泌颗粒的转运。GBF1 调节 ER 和 TGN 出口，后者显著影响 VWF 储存细胞器的大小，从而影响内皮的止血能力。AMPK 作为细胞内和细胞外信号的中心整合元件在细胞途径中的作用现在可以扩展到对顺行分泌途径的调节。
