Inserm U. 348, hôpital Lariboisière, 2, rue Ambroise-Paré, 75475 Paris cedex 10, France.
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.