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Arterioscler Thromb Vasc Biol. 2018 May;38(5):1037-1051. doi: 10.1161/ATVBAHA.117.310373. Epub 2018 Mar 8.

Kinesin-1 Is a New Actor Involved in Platelet Secretion and Thrombus Stability.

Author information

1
From the INSERM, UMR_S 1176, Paris-Sud University, Université Paris-Saclay, Le Kremlin-Bicêtre, France (F.A., A.K., M.B., D.B., O.D.C.) frederic.adam@inserm.fr.
2
From the INSERM, UMR_S 1176, Paris-Sud University, Université Paris-Saclay, Le Kremlin-Bicêtre, France (F.A., A.K., M.B., D.B., O.D.C.).
3
INSERM, UMR_S 1163, Laboratory of Normal and Pathological Homeostasis of the Immune System, Paris, France (M.K., I.M., A.F., G.d.S.B., G.M.).
4
Imagine Institute (M.K., I.M., A.F., G.d.S.B., G.M.).
5
Cell Imaging Facility, Imagine Institute (N.G.), Paris Descartes University, Sorbonne Paris Cité, France.
6
Laboratoire d'Hémostase, Centre de Biologie Est, Hospices Civils de Lyon, Bron, France (J.-C.B.).
7
Laboratoire de Recherche sur l'Hémophilie, UCBL1, Lyon, France (J.-C.B.).
8
School of Biomedical Sciences, The University of Hong Kong, China (J.-D.H.).
9
Department of Immunology and Pediatric Hematology (A.F.).
10
Biological Hematology Service (D.B.), Necker Children's Hospital, Assistance Publique-Hôpitaux de Paris, France; and Collège de France, Paris (A.F.).

Abstract

OBJECTIVE:

Platelet secretion is crucial for many physiological platelet responses. Even though several regulators of the fusion machinery for secretory granule exocytosis have been identified in platelets, the underlying mechanisms are not yet fully characterized.

APPROACH AND RESULTS:

By studying a mouse model (cKO [conditional knockout]Kif5b) lacking Kif5b (kinesin-1 heavy chain) in its megakaryocytes and platelets, we evidenced unstable hemostasis characterized by an increase of blood loss associated to a marked tendency to rebleed in a tail-clip assay and thrombus instability in an in vivo thrombosis model. This instability was confirmed in vitro in a whole-blood perfusion assay under blood flow conditions. Aggregations induced by thrombin and collagen were also impaired in cKOKif5b platelets. Furthermore, P-selectin exposure, PF4 (platelet factor 4) secretion, and ATP release after thrombin stimulation were impaired in cKOKif5b platelets, highlighting the role of kinesin-1 in α-granule and dense granule secretion. Importantly, exogenous ADP rescued normal thrombin induced-aggregation in cKOKif5b platelets, which indicates that impaired aggregation was because of defective release of ADP and dense granules. Last, we demonstrated that kinesin-1 interacts with the molecular machinery comprising the granule-associated Rab27 (Ras-related protein Rab-27) protein and the Slp4 (synaptotagmin-like protein 4/SYTL4) adaptor protein.

CONCLUSIONS:

Our results indicate that a kinesin-1-dependent process plays a role for platelet function by acting into the mechanism underlying α-granule and dense granule secretion.

KEYWORDS:

blood platelets; hemostasis; kinesin; platelet secretion

PMID:
29519941
DOI:
10.1161/ATVBAHA.117.310373

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