Intracellular storage of secretory proteins in the megakaryocytic lineage Volume 8, issue 5, Septembre - Octobre 2002
- Key words: PF4, alpha granule, storage pool disease, Weibel-Palade body, trans-Golgian net, E carboxypeptidase.
- Page(s) : 349-58
- Published in: 2002
Platelets act in hemostasis, wound healing, and inflammation, in part through release of their secretory granules, consisting in dense granules, lysosomes and alpha granules. Platelet secretory proteins (PF4, vWF, t-PA, etc.) are electively stored in alpha granules, the focus of the present review. Several human bleeding disorders alter granular storage, including the Griscelli, the Hermansky-Pudlak and the Chediak-Higashi Syndromes which alter dense granule and lysosome storage in platelets; the delta and alphadelta platelet storage pool defects, where delta granules, and in some cases both alpha and delta granules are absent; however, only the Gray Platelet Syndrome (GPS) affects specifically alpha granules, which are devoid of secretory proteins. We propose a model in which alpha granule secretory proteins are selected by a sorting receptor in the Golgi of the megakaryocyte, coupled to the vesicle budding machinery (involving adpator molecules, coat proteins, rab G-proteins and molecular motors). We suggest that GPS may be due to a misrouting of secretory proteins, because of the alteration of this sorting machinery. Future studies will be aimed at testing this hypothesis. Weibel-Palade bodies (WPB) are endothelial cell storage granules, thought to be analogous to platelet alpha granules, since they store vWF and the membrane receptor P-selectin. To test this hypothesis, PF4, a megakaryocyte-specific alpha granule protein, was transfected into Huvecs. Our results show that PF4 does not traffick along with vWF into WPB and identifies a different granule storage pool containing t-PA. We conclude that the biogenesis of these two storage organelles is, at least in part, different. We propose a model in which immature secretory granules bud from the Golgi apparatus in both cell types: while in the megakaryocytic lineage, immature granules will eventually all merge into the alpha granule, in endothelial cells, immature vWF-containing granules will fuse independently from the t-PA-containing granule pool, to form WPB. Future studies to identify megakaryocytic and endothelial molecular partners involved in secretory proteins storage, will allow a better understanding of i) storage diseases such as GPS; ii) the mechanism of storage granule biogenesis of both megakaryocytic and endothelial cells.