Coactosin-like 1 integrates signaling critical for shear-dependent thrombus formation in mouse platelets
Scheller I, Stritt S, Beck S, Peng B, Pleines I, Heinze KG, Braun A, Otto O, Ahrends R, Sickmann A, Bender M, Nieswandt B (2020)
Publication Type: Journal article
Publication year: 2020
Journal
Book Volume: 105
Pages Range: 1667-1676
Journal Issue: 6
DOI: 10.3324/haematol.2019.225516
Abstract
Platelet aggregate formation is a multistep process involving receptormediated, as well as biomechanical, signaling cascades, which are highly dependent on actin dynamics. We have previously shown that actin depolymerizing factor (ADF)/n-cofilin and Twinfilin 2a, members of the ADF homology (ADF-H) protein family, have distinct roles in platelet formation and function. Coactosin-like 1 (Cotl1) is another ADF-H protein that binds actin and was also shown to enhance biosynthesis of pro-inflammatory leukotrienes (LT) in granulocytes. Here, we generated mice lacking Cotl1 in the megakaryocyte lineage (Cotl1-/-) to investigate its role in platelet production and function. Absence of Cotl1 had no impact on platelet counts, platelet activation or cytoskeletal reorganization under static conditions in vitro. In contrast, Cotl1 deficiency markedly affected platelet aggregate formation on collagen and adhesion to immobilized von Willebrand factor at high shear rates in vitro, pointing to an impaired function of the platelet mechanoreceptor glycoprotein (GP) Ib. Furthermore, Cotl1-/- platelets exhibited increased deformability at high shear rates, indicating that the GPIb defect may be linked to altered biomechanical properties of the deficient cells. In addition, we found that Cotl1 deficiency markedly affected platelet LT biosynthesis. Strikingly, exogenous LT addition restored defective aggregate formation of Cotl1-/- platelets at high shear in vitro, indicating a critical role of platelet-derived LT in thrombus formation. In vivo, Cotl1 deficiency translated into prolonged tail bleeding times and protection from occlusive arterial thrombus formation. Together, our results show that Cotl1 in platelets is an integrator of biomechanical and LT signaling in hemostasis and thrombosis.
Involved external institutions
Julius-Maximilians-Universität Würzburg
Germany (DE)
Leibniz-Institut für Analytische Wissenschaften / Leibniz Institute for Analytical Sciences (ISAS)
Germany (DE)
Universität Greifswald
Germany (DE)
Germany (DE)
Leibniz-Institut für Analytische Wissenschaften / Leibniz Institute for Analytical Sciences (ISAS)
Germany (DE)
Universität Greifswald
Germany (DE)
How to cite
APA:
Scheller, I., Stritt, S., Beck, S., Peng, B., Pleines, I., Heinze, K.G.,... Nieswandt, B. (2020). Coactosin-like 1 integrates signaling critical for shear-dependent thrombus formation in mouse platelets. Haematologica, 105(6), 1667-1676. https://doi.org/10.3324/haematol.2019.225516
MLA:
Scheller, Inga, et al. "Coactosin-like 1 integrates signaling critical for shear-dependent thrombus formation in mouse platelets." Haematologica 105.6 (2020): 1667-1676.
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