Summary 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. Graphical Abstract Highlights • The Arf-GEF GBF1 modulates anterograde trafficking of VWF and ECM proteins • Loss of GBF1 slows ER and TGN exit, producing swollen ER and giant WPBs • Activation of GBF1 via AMPK reduces endothelial WPB size and secretion • Metabolic change alters anterograde trafficking and cargo secretion via AMPK-GBF1 da Silva et al. examine how the secretory pathway is coupled to environmental cues. They show that suppression of GBF1, the GEF for two Golgi Arfs (1 and 4), slows exit from the ER and the TGN. GBF1 can be phosphorylated by AMPK, and metabolic activation or inhibition of AMPK controls anterograde traffic.
【저자키워드】 Hemostasis, AMPK, endothelial cells, von Willebrand factor, Golgi, collagen, secretion, GBF1, anterograde trafficking, organelle size,